201113049 六、發明說明： 【發明所屬之技術領域】 本發明係有關藉由將水溶性藥物及難溶性藥物，及具 各種物性之安定化劑及氧化劑等製劑添加物進行奈米分散 於相同分散媒中，使顯示2種以上相異物性的藥物及製劑 添加物配合於單一製劑中之技術。 【先前技術】 在治療中，與其說將醫藥品以單劑進行投藥相當罕見 ，不如說大部分的狀況是因應治療階段，相當普遍地將複 數種治療藥物複合式地進行投藥。以手術爲例，在術前、 術中、術後各階段，爲及早恢復且防止休克，以預防感染 爲目的’在由靜脈管注射糖及胺基酸輸液等點滴時，大多 會由側管注入抗生素等。 進行點滴或側管注射時，醫藥品必須爲可溶化者，進 而可說是希望是在中性範圍可溶解者，而不溶性藥物不僅 無法進行投藥，或即便爲可溶性藥物，在中性範圍無法溶 解的藥物，其投藥是治療上相當惱人的問題。 以該種於中性範圍附近不會溶解的藥物爲首，有許多 如上所述的難溶性藥物，由於非常難以將該等藥物與注射 劑配合，爲將顯示相異物性的水溶性藥物與難溶性藥物溶 解於水中，只有添加界面活性劑，將其製爲乳濁液之乳化 物此一方法。然而，乳濁液不僅會因加熱膨脹而損壞，時 間一久’必會分離爲沉澱物與澄清液2層，非常難以進行 -5- 201113049 調整。 如此謹慎地存在之相異物性的藥物之最易理解的例子 ，可舉出自醫藥品、食品至化妝品，廣泛被使用的營養因 子。例如輔酵素維他命，存在有已知爲腳氣病病因因子的 維他命B1、壞血症病因的維他命C等水溶性維他命，另外 還存在有夜盲症病因的維他命A、可促進鈣質吸收的維他 命D、及具有血管擴張作用的維他命E等難溶性（脂溶性） 維他命。 同樣的，人體所必須的20個胺基酸中，8個是疏水性 胺基酸，其他則爲親水性胺基酸。特別爲人體無法合成的 9種胺基酸中，除親水性的離胺酸、穌胺酸、組胺酸之外 ，纈胺酸、白胺酸、異白胺酸、甲硫胺酸、苯丙胺酸、色 胺酸等6種胺基酸爲疏水性等，可明確得知在相同的營養 因子中，存在有顯示2種相異物性者。 如此，以醫藥品爲首，於含有營養因子等醫療輔助製 品之『藥物』中，謹慎地存在水溶性、難溶性2種相異的 藥物，對於使用注射劑、輸液、內服液、乳液、泥罨劑、 敷糊劑等液劑及水溶性基劑之劑型的調製，或於調製油性 注射劑、油性膠囊製劑、油性外用劑、硬膏製劑時，造成 很大的問題。 例如乳液、泥罨劑、敷糊劑、油性外用劑及硬膏製劑 等外用劑係塗佈於皮膚或貼付於皮膚上。調製該等製劑時 ，以往無法將具有相異物性之藥物，以可發揮藥物所具有 的功能的型態，調製爲一劑型之製劑。換言之，皮膚是生 -6- 201113049 物體最大的屏障，爲疏水性極高的組織，由至今尙未開發 水溶性醫藥品，或被利用爲醫療輔助製品之水溶性維他命 類等外用劑的事實，可以充分理解》亦即，由於一般人體 皮膚係表皮細胞以28天的週期，由角質細胞代謝爲角質之 生理性的再生組織，只要供給該表皮組織與年齡無關的必 需的營養條件，即可培養表皮細胞，並使其增生，而人體 皮膚組織亦爲只要可以接受到來自血液充分的營養補給， 應可再生爲正常的皮膚，然而，由於醫療現場無法提供以 可發揮水溶性維他命類等功能之型態的外用劑，現狀是可 發現以異位性皮膚炎、乾癖爲始的各式各樣的皮膚疾病。 皮膚營養障礙有各種理由，例如一般認爲由於原因爲 低血壓及微血管缺血狀態所造成的皮膚營養不足，無法進 行正常的皮膚組織再生，及因角質層與表皮細胞層分化速 度的差異等而發生皮膚疾病，爲改善此現象僅有藉由血管 擴張劑使血流量增加，或將作用相同且含脂溶性維他命E 之外用劑塗佈於皮膚上的治療方法。 實際上，若能實現經由角質層直接將營養因子送達皮 膚組織的經皮投藥則十分慶幸，但皮膚組織原爲疏水性的 屏障，無法吸收水溶性的維他命及胺基酸等，無怪乎只有 難溶性（脂溶性）的維他命外用劑。 因此，爲供應皮膚組織所必需的水溶性維他命及胺基 酸等營養成分，亦即爲投藥營養因子，僅有改變使用脂溶 性高之衍生物而配合於外用劑中，或爲使其經口攝取之投 藥方法。長久以來盼望出現並非將水溶性維他命類進行衍 201113049 生物化，而是將其表面物性轉變爲脂溶性化，使脂溶性維 他命類配合於一劑型之油性基劑中之技術。 另一方面，將含維他命之輔酵素及胺基酸等營養因子 製品化時，水溶性及難溶性此二相異的物性、安定性、風 味、臭味等成爲開發製劑及製品上的問題。含維他命之輔 酵素係指於生物體內酵素爲發揮其活性所必需的輔酵素。 其缺乏症會出現在與利用該輔酵素之酵素相關的代謝系之 功能不全。 維他命可分類爲易溶於水的水溶性及易溶於脂的脂溶 性。水溶性維他命有維他命B群（Bl、B2、B3、B5、B6、 B7、B9、B12)及維他命C»脂溶性維他命有維他命A、維 他命D、維他命E及維他命K。維他命B1又稱爲硫胺素，B2 則爲核醣黃素，B3爲菸鹼酸，B5爲泛酸，B6爲抗皮炎素 ，B 7爲生物素，B 9爲葉酸，B 1 2則爲氰鈷胺素，維他命C 則又稱做抗壞血酸。 維他命類的營養因子除上述維他命外，尙包含各種維 他命衍生物及輔酵素類。可舉出維他命A類有各種類胡蘿 蔔素，維他命D類有各種鈣化固醇，維他命E類有各種生育 醇，維他命K類有各種萘醌衍生物。維他命以外的輔酵素 可舉出水溶性的乳清酸及泛配子酸、苦杏仁素、抗潰瘍素 、肉鹼等。脂溶性的輔酵素可舉出亞麻油酸等必須脂肪酸 、槲黃素、泛醌等醌輔酵素。泛醌又稱爲輔酵素Q10( CoQlO )。胺基酸、礦物質、糖類分類於水溶性營養因子 。另外脂質被分類於脂溶性的營養因子。脂質可舉出各種 -8- 201113049 多酚、種子油萃取成分、芝麻類、二十碳五烯酸、蜂膠等 。如此以一種營養因子爲例，既存在有水溶性者，亦存在 有脂溶性者，以將該等成分因應使用目的組合使用爲佳。 調製注射劑、輸液、內服液、點眼劑、點鼻劑或水性 的化妝水等時，對具有相異物性的2個以上的成分，會將 水溶性成分直接溶解於水溶性基劑，難溶性成分則改變其 表面物性爲親水性，以藥物-界面活性劑複合體之形式配 合成爲一劑型。於水溶性溶媒中混合產生變化的水溶性的 2成分中，藉由使其中之一爲親水性的藥物-界面活性劑 複合體，而防止2成分直接接觸，且可防止配合變化。 [先前專利文件] [專利文件] [專利文件1]特開2004-433 55 [專利文件2]國際公開編號W02005/0 94789 [專利文件3]國際公開編號W02006/0 25583 [專利文件4]特開2004-8837 [非專利文件] [非專利文件1]日本藥理誌（Folia Pharmacol. Jpn.) 127;213-216 (2006) [非專利文件2]第36次SPG硏討會演講摘要集，50-53 (2001) [非專利文件 3]International Journal of Pharmaceutics -9 - 201113049 252; 271-274 (2003) [非專利文件4]International Journal of Pharmaceutics 3 3 8; 1 74- 1 79 (2007) [非專利文件 5]Pharmaceutical Development and Technology 12; 321-325 (2007) 【發明內容】 [發明欲解決之課題] 使用於醫藥品，或醫藥品•食品•化妝品之如同營養 因子般的『醫療輔助製品』，進而製劑添加物可分爲水溶 性與難溶性，但要將水溶性物質分散於已溶解難溶性物質 之油性製劑十分困難，同樣的，要將難溶性物質均勻分散 混合於由水溶性物質所構成之水性注射劑及內服液劑等之 中，亦非常困難。 另外，『藥物』，即醫藥品、醫療輔助製品及其二者 ，會由於爲了製造其之製劑添加劑爲水溶性或難溶性，而 難以使複數種藥物配合於相同分散媒。本發明係藉由計畫 將意圖配合之複數種藥物的物性均勻化，著力於爲將物性 相異之至少2種以上之藥物，分散配合於同一種溶媒，進 而抑制配合所產生的變化，提高安定性及增加對生物體之 吸收性，且抑制副作用，及計畫用於掩蔽苦澀味或臭味等 之解決方法，將顯示水溶性或難溶性之相異物性的複數種 藥物其中之一，或將二者均製作爲內包於S/W、S/Ο或 S/0/W之界面活性劑的藥物-界面活性劑複合體，因應製 -10- 201113049 劑目的，製造及提供奈米分散於水溶性基劑或油性基劑任 一分散媒中之醫藥品，或醫療輔助製品。 特別係含有水溶性維他命及胺基酸等之醫藥品或醫療 輔助製品，由於原本不具有經皮吸收性，藉由將該等之親 水性藥品或醫療輔助製品以界面活性劑包覆，以藥物-界 面活性劑複合體之形式使其物性改變爲脂溶性，可計畫藥 物之安定化及提高經皮吸收性，進而可期待由加入了 1種 以上之脂溶性藥物，或醫療輔助製品原料所構成之配合劑 之醫藥品製劑，以及醫療輔助製品之開發，且可使用爲油 性製劑。例如目前正期望將水溶性維他命C的表面改變爲 脂溶性，再與脂溶性的維他命E進行配合而製作爲一劑型 的油性製劑之技術。將水溶性維他命C的表面改變爲脂溶 性，進而將水溶性的羥基脯胺酸的表面轉變爲脂溶性，藉 由將兩者進行配合而製作爲一劑型的油性製劑，正期盼著 對皮膚具有相乘性的效果，且可期待恢復肌膚活力及具創 傷治療效果的製劑。而該等課題藉由本發明已獲得解決。 進而藉由將難溶性藥物製造爲以親水性界面活性劑包 覆之藥物-界面活性劑複合體，期望可製造注射劑、輸液 、內服液劑及水溶性凝膠內服劑、或外用凝膠乳霜，以及 使用陰離子系之高親水性界面活性劑之化妝水、電氣誘導 用液劑及凝膠劑。例如期望將輔酶Q表面改變爲親水性， 製作爲溶解於水溶性凝膠之凝膠內服劑。另外亦期望製造 溶解於離子電泳用電極水溶液中，可使肌膚彈力復活之製 劑。該等課題藉由本發明已獲得解決。 -11 - 201113049 因應目的，藉由將藥物表面變更爲親水性、脂溶性， 使複數種藥物的表面物性均一化，可製作水溶性或脂溶性 之任一種製劑。藉由使藥物具有親水性不僅可期待可溶解 於水溶性溶媒，還可進行離子化。 另外，由於可將2種以上相異物性之藥物，安定配合 於任一者的分散媒中，可防止進行製劑化懸濁粉體時所見 之含量不均，及因加熱處理步驟與經時變化所產生的沉降 及相分離。另外藉由使用本技術，因可防止會引起配合變 化之藥物直接接觸，而可抑制配合變化。 配合變化之例可舉出例如維他命C與重亞硫酸鈉之加 成反應，胺基酸、含胺基藥物與糖類、含醛基藥物之胺羰 反應，含硫酸基之化合物與具胺基藥物之沉澱反應，鹽酸 特比萘芬與氯化苯二甲烴銨等。其他則可舉出聚乙二醇與 苯巴比妥、聚乙二醇與長春花生物鹼類藥劑之配合變化， 二丁基羥基甲苯與具胺之化合物之配合變化，氨基菲林與 葡萄糖所產生之席夫鹼基，四環黴素與鹼土類金屬之糠醛 反應，腎上腺素因亞硫酸基之外消旋體化，苯若可因與檸 檬酸形成之酸性胺，甲黴素與卡苯尼西林形成複合體，阿 斯匹靈與苯腎上腺素所產生之胺解反應，相同的綜合維他 命劑之異性化等。目前正期望克服該等課題之技術。而本 方法可將其中一成分之表面或二種成分之表面，藉由以界 面活性劑進行包覆製成藥物-界面活性劑複合體，而可抑 制該等配合變化。 將難溶性藥物與水溶性藥物、難溶性藥物與難溶性藥 -12- 201113049 物、水溶性藥物與水溶性藥物配合而成爲一劑型，提高彼 此藥物的效果且抑制副作用之例有高血脂症治療劑之二十 碳五烯酸與立普妥之配合，維他命K2與爲質子幫浦阻斷劑 之泰克胃通之配合，鈣離子擷抗劑與ACE阻礙劑之配合， 易寧神注射液與易寧優錠之配合，維他命E與維他命C之配 合’維他命A與維他命C之配合，硬酯酸抗壞血酯與抗壞血 酸及磷酸硬酯醇鎂，輔酶Q10與磷酸硬酯酸醇鎂之配合， 克炎栓劑與抑疼炎栓劑之配合。然而根據以往的方式使用 液劑的形式進行配合時，無論水溶性溶媒或脂溶性溶媒， 其中之一藥物出現沉澱 '浮游、或形成凝集塊，抑或與製 劑添加劑配合時引起變化等，無法開發出高含量均一性之 製劑。而本方法可將其中一成分之表面或二種成分之表面 ，藉由以界面活性劑進行包覆製成藥物-界面活性劑複合 體，而使該等成分可進行配合而製成一劑型化。 [解決課題之手段] 亦即爲解決相關課題，製造將藥物內包於界面活性劑 之藥物-界面活性劑複合體，因應目的，藉由將其製作爲 可微小分散於親水性溶媒之S/W、或可分散於脂溶性溶媒 之S/0、及進而可分散於親水性溶媒之S/0/W製劑及製品， 可使複數種藥物配合於相同的分散媒（親水性溶媒、水溶 性溶媒及脂溶性溶媒）中。 亦即本發明係如下所述。 (1 ) 一種製劑，其係將水溶性藥物及難溶性藥物溶 -13- 201113049 解或分散於選自親水性溶媒或脂溶性溶媒之任一種溶媒中 〇 (2 )如上述（1 )項之製劑，其中水溶性藥物及難溶 性藥物係分別選自醫藥品、營養因子、製劑添加物及該等 之任意組合者。 (3)如（1 )或（2 )項之製劑，其中該難溶性藥物 ，對pH 1.0〜7.5之25 0ml緩衝液之溶解度係顯示1單位製劑 中所含最大藥物含量以下之溶解度，相當於BCS ( Biopharmaceutical Classification System，藥品溶解度及 穿透性分類原則）之Low Solubility ( LS)者。 (4 )如（1 )項之製劑，其中水溶性藥物或難溶性藥 物係以固體狀態進行內包之藥物-界面活性劑複合體（以 下略記做Solid或S)。 (5) 如上述（1)至（4)項中任一項之製劑，其中 難溶性藥物係疏水性難溶性藥物，該難溶性藥物係藥物-界面活性劑複合體（Solid )分散於水相（Water )之 Solid-in-Water ( S/W)型態。 (6) 如（1)至（4)項中任一項之製劑，其中水溶 性藥物係藥物-界面活性劑複合體（Solid)分散於油相（ Oil)之 Solid-in-Oil ( S/O)型態。 (7) 如（1)至（4)項中任一項之製劑，其中難溶 性藥物係親水性難溶性藥物，該難溶性藥物係藥物-界面 活性劑複合體（Solid)分散於油相（Oil)之s〇lid-in-0il (S/0)型態。 14- 201113049 (8 )如（1 )至（4 )項中任一項之製劑，其中水溶 性藥物係藥物一界面活性劑複合體（Solid )分散於油相（ Oil)之Sol id-in-Oil ( S/0)型態，進而將該油相分散於水 相中，爲 Solid-in-Oil-in-Water ( S/0/W )型態。 (9)如（1)至（4)項中任一項之製劑，其中難溶 性藥物係親水性難溶性藥物，該難溶性藥物係藥物-界面 活性劑複合體（Solid )分散於油相（Oil )，進而將該油 相分散於水相中，爲Solid-in-Oil-in-Water (S/0/W)型態 〇 (1 0 )如（1 )至（4 )項中任一項之製劑，其中水溶 性藥物係被溶解於親水性溶媒中，難溶性藥物係疏水性難 溶性藥物，且該疏水性難溶性藥物係以藥物-界面活性劑 複合體（Solid)分散於水相（Water)之 Solid-in-Water( S/W)之型態，被分散於親水性溶媒中。 (11)如（1)至（4)項中任一項之製劑，其中水溶 性藥物係以藥物-界面活性劑複合體（Solid )分散於油相 (Oil )之Solid-in-Oil ( S/Ο )之型態，被分散於脂性溶媒 中，難溶性藥物係疏水性難溶性藥物，且被溶解於脂性溶 媒中。 (12 )如（1 )至（4 )項中任一項之製劑，其中水溶 性藥物係以藥物-界面活性劑複合體（Solid)分散於油相 (Oil )之Solid-iii-Oil ( S/Ο )，再進而分散於水相之 Solid-in-〇il-in-Water (S/0/W)之型態，被分散於親水性 溶媒中，難溶性藥物係疏水性難溶性藥物，且該疏水性難 -15- 201113049 溶性藥物係以藥物-界面活性劑複合體（Solid )溶解或分 散於水相（Water )之Sol id-in-Water ( S/W )之型態，被 分散於親水性溶媒中。 (1 3 )如（1 )至（4 )項中任一項之製劑，其中水溶 性藥物係以藥物-界面活性劑複合體（Solid )分散於油相 (Oil )之Solid-in-Oil ( S/0 )之型態，被分散於脂溶性溶 媒中，難溶性藥物係親水性難溶性藥物，且以藥物-界面 活性劑複合體（Solid)分散於油相（Oil)之Solid-in-Oil (S/O )之型態，被分散於脂溶性溶媒中。 (14)如（1)至（4)項中任一項之製劑，其中水溶 性藥物係被溶解於親水性溶媒中，親水性難溶性藥物係以 藥物一界面活性劑複合體（Solid)分散於油相（Oil)之 Solid-in-Oil ( S/0 )，再進而分散於水相中之8〇1丨(1411-Oil-in-Water ( S/0/W)之型態，被分散於親水性溶媒中。 (1 5 )如（1 )至（4 )項中任一項之製劑，其中水溶 性藥物被分散於水性凝膠中，難溶性藥物係親水性難溶性 藥物，以藥物_界面活性劑複合體（Solid )分散於水相（ Water)之Solid-in-Water (S/W)之型態，被分散於水性 凝膠中。 (16 )如（1 )至（1 5 )項中任一項之製劑，其中該 藥物係選自具有藥理學活性、治療性、診斷性、或預防性 活性物質之醫藥品。 (1 7 )如（1 )至（1 5 )項中任一項之製劑，其中該 藥物係選自胺基酸、含維他命之輔酵素、礦物質、脂質或 -16- 201113049 糖之營養因子。 (1 8 )如（1 )至（1 5 )項中任—項之製劑，其中該 藥物係選自安定化劑、抗氧化劑、著色劑、防腐劑、保存 劑、無痛化劑、緩衝劑' 胺基酸、含維他命之輔酵素、礦 物質、脂質或糖之製劑添加物。 (1 9 ) 一種配合劑之製造方法，其特徵係可使疏水性 難溶性藥物及S/ο ( Solid-in-Oil)化之水溶性藥物分散於 脂溶性溶媒中。 (20)—種配合劑之製造方法，其特徵係可使水溶性 藥物及Solid-in-Water ( S/W)化之疏水性難溶性藥物均勻 地分散於親水性溶媒中。 (21 ) —種配合劑之製造方法，其特徵係可使S〇nd_ in-Oil-in-Water (S/0/W)化之水溶性藥物，以及 s〇lid-in-Water ( S/W )化之疏水性難溶性藥物均勻地分散於親水性 溶媒中。 (22 ) —種配合劑之製造方法，其特徵係可使S/O ( Solid-in-Oil)化之水溶性藥物，以及 S/O ( Solid-in-Oil) 化之親水性難溶性藥物均勻地分散於脂溶性溶媒中。 (23) —種配合劑之製造方法，其特徵係可使水溶性 藥物，以及Solid-in-Oil-in-Water ( S/0/W)化之親水性難 溶性藥物均勻地分散於親水性溶媒中。 (24) —種配合劑之製造方法，其特徵係可使水溶性 藥物與Solid-in-Water ( S/W )化之親水性難溶性藥物均句 地分散於親水性溶媒中。 -17- 201113049 (25 ) —種含有藥物-界面活性劑複合體之製品，其 係將含有使水溶性藥物及難溶性藥物S/W ( Solid-in-Water )化後所製成之藥物-界面活性劑複合體之離子電滲用電 極水溶液，作爲離子電滲療法之含有藥物水溶液。 (26 ) —種醫藥品，其特徵係含有如（1 )至（1 8 ) 項中任一項之製劑。 (27 )—種食品，其特徵係含有（1 )至（18 )項中 任一項之製劑。 (2 8 ) —種化妝品，其特徵係含有如（1 )至（1 8 ) 項中任一項之製劑。 (29 )—種製劑，其特徵係將水溶性藥物S/0化後， 與疏水性難溶性藥物一同均勻地分散於油脂中，並將其塡 充於軟膠囊或硬膠囊中而成型。 (30 ) —種脂溶性溶媒，其特徵係將水溶性藥物S/O 化後均勻地分散於脂溶性溶媒中，進而將經S/0化之親水 性難溶性藥物，或疏水性難溶性藥物懸濁或分散於脂溶性 溶媒中。 (31 ) —種製劑，其特徵係將如（29 )至（30 )項中 之脂溶性溶媒，塡充於軟膠囊或硬膠囊中而成型。 (3 2 ) —種製品，其特徵係將如（3 1 )項之塡充於軟 膠囊或硬膠囊中而成型之製劑，以易撕型或擠壓型之氣泡 包裝進行包裝。 (33 ) —種製劑，其特徵係將水溶性藥物及/或難溶 性藥物以固體狀態進行內包之藥物-界面活性劑複合體（ -18- 201113049 以下略記做Solid或S )，均勻分散於水性凝膠劑中，再將 其塡充至定量容器中而成型。 (34) —種製劑，其特徵係對無法共存於單一溶媒之 複數種藥物，將每種藥物製爲藥物-界面活性劑複合體， 使可分散於該溶媒中。 (35) 如（34)項中之製劑，其中該複數種藥物均爲 水溶性藥物，將每種藥物製爲藥物_界面活性劑複合體（ LipoS )分散於油相（Oil )中，以 Solid-in-Oil ( S/O )之 型態分散於脂溶性溶媒中。 (36) 如（34)項中之製劑，其中該複數種藥物均爲 水溶性藥物，將每種藥物製爲藥物-界面活性劑複合體（ LipoS)分散於油相（Oil)之 Solid-in-Oil (S/0)，再進 而以分散於水相之Sol id-in-Oil-in-Water ( S/0/W )之型態 ，分散於親水性溶媒中。 (37) 如（34)項中之製劑，其中該複數種藥物均爲 疏水性難溶性藥物，將每種藥物製爲藥物-界面活性劑複 合體（Hydros )分散於水相（Water )後，以Solid-in-Water ( S/W )之型態，分散於親水性溶媒中。 (38) 如（34)項中之製劑，其中該複數種藥物均爲 親水性難溶性藥物，將每種藥物製爲藥物-界面活性劑複 合體（LipoS)分散於油相（Oil)之 Solid-in-Oil (S/0) ，再進而以分散於水相之3〇1丨(1-丨11-0丨1-丨11-1^3161'(3/0/评） 之型態，分散於親水性溶媒中。 (39) 如（34)項中之製劑，其中該複數種藥物均爲 -19- 201113049 親水性難溶性藥物，將每種藥物製爲藥物-界面活性劑複 合體（Solid)，以分散於水相（Water)之 Solid-in-Water (S/W )之型態被分散於水性凝膠中。 (40 )如（34 )至（39 )項中任一項之製劑，其中該 複數種藥物係於溶媒中引起化學反應之藥物。 (41 )如（34)至（39)項中任一項之製劑，其中該 複數種藥物係含有具氧化作用之藥物以及具還原作用之藥 物。 (42 )如（3 4 )至（3 9 )項中任一項之製劑，其中該 複數種藥物係含有含金屬離子之藥物與形成錯合物之藥物 〇 (43) —種製劑之製造方法，其特徵係包含對無法共 存於單一溶媒之複數種藥物，將每種藥物調製爲藥物一界 面活性劑複合體，再將該藥物-界面活性劑複合體分散於 溶媒中。 (44) 如（43)項中之製劑之製造方法，其中該複數 種藥物均爲水溶性藥物，將每種藥物製爲藥物-界面活性 劑複合體（LipoS)，以分散於油相（Oil)之Solid-in-Oil (S/0 )之型態，分散於脂溶性溶媒中》 (45 )如（43 )項中之製劑之製造方法，其中該複數 種藥物均爲水溶性藥物，將每種藥物製爲藥物-界面活性 劑複合體（LipoS )分散於油相（Oil )之Solid-in-Oil ( S/Ο )，再進而以分散於水相之Solid-in-Oil-in-Water ( S/0/W)之型態，分散於親水性溶媒中。 -20- 201113049 (46) 如（43)項中之製劑之製造方法，其中該複數 種藥物均爲疏水性難溶性藥物，將每種藥物製爲藥物-界 面活性劑複合體（Hydros )分散於水相（Water )，以 Solid-in-Water ( S/W)之型態，分散於親水性溶媒中。 (47) 如（43)項中之製劑之製造方法，其中該複數 種藥物均爲親水性難溶性藥物，將每種藥物製爲藥物-界 面活性劑複合體（LipoS)分散於油相（Oil)之Solid-in-〇il ( S/O )，進而以分散於水相之 Solid-in-Oil-in-Water ( s/0/w)之型態，分散於親水性溶媒中。 (48 )如（43 )至（47 )項中任一項之製劑之製造方 法，其中該複數種藥物係於溶媒中引起化學反應之藥物。 (49 )如（43 )至（47 )項中任一項之製劑之製造方 法，其中該複數種藥物係含有具氧化作用之藥物以及具還 原作用之藥物。 (50 )如（43 )至（47 )項中任一項之製劑之製造方 法，其中該複數種藥物係含有含金屬離子之藥物與形成錯 合物之藥物。 (51) —種藥物掩蔽或防臭之方法，其特徵係將藥物 製爲藥物-界面活性劑複合體之型態分散於溶媒中。 (52) —種藥物之安定化方法，其特徵係藉由將藥物 製爲藥物-界面活性劑複合體之型態分散於溶媒中》 發明的效果 本發明係藉由製作將藥物內包於界面活性劑之藥物- -21 - 201113049 界面活性劑複合體，使藥物的物性均一化，可被微分散於 親水性或脂溶性溶媒中，進而計畫安定性及提高吸收性， 且可掩蔽苦澀味或臭味等，並且，可於同一種分散溶媒， 將物性相異之藥物，或可配合2種以上之藥物-界面活性 劑複合體之醫藥品製劑或醫療輔助製品等，提供含有藥物 -界面活性劑複合體之製品。 本發明係可將顯示相異物性的藥物之物性均一化，安 定且吸收性佳，進而可計畫改善苦味及苦澀味或臭味等。 另外可因應目的，藉由將藥物表面變更爲親水性、脂 溶性，使複數種藥物的表面物性均一化，可製作水溶性或 脂溶性之任一種製劑。藉由使藥物具有親水性不僅可期待 可溶解於水溶性溶媒，亦可進行離子化。 另外，由於可將2種以上相異物性之藥物，安定配合 於任一者的分散媒中，可防止進行製劑化懸濁粉體時所見 之含量不均，及因加熱處理步驟與經時變化所產生的沉降 及相分離。另外藉由使用本技術，因可防止會引起配合變 化之藥物直接接觸，而可抑制配合變化。 配合變化之例可舉出例如維他命C與重亞硫酸鈉之加 成反應，胺基酸、含胺基藥物與糖類、含醛基藥物之胺羰 反應，含硫酸基之化合物與具胺基藥物之沉澱反應，鹽酸 特比萘芬與氯化苯二甲烴銨等。其他則可舉出聚乙二醇與 苯巴比妥、聚乙二醇與長春花生物鹼類藥劑之配合變化， 二丁基羥基甲苯與具胺之化合物之配合變化，氨基菲林與 葡萄糖所產生之席夫鹼基，四環黴素與鹼土類金屬之糠醛 -22- 201113049 反應，腎上腺素因亞硫酸基之外消旋體化，苯若可因與檸 檬酸形成之酸性胺，甲黴素與卡苯尼西林形成複合體，阿 斯匹靈與苯腎上腺素所產生之胺解反應，相同的綜合維他 命劑之異性化等。目前正期望克服該等課題之技術。而本 方法可將其中一成分之表面或二種成分之表面，藉由以界 面活性劑進行包覆製成藥物-界面活性劑複合體，而可抑 制該等配合變化》 將難溶性藥物與水溶性藥物、難溶性藥物與難溶性藥 物、水溶性藥物與水溶性藥物配合而成爲一劑型，提高彼 此藥物的效果且抑制副作用之例有高血脂症治療劑之二十 碳五烯酸與立普妥之配合，維他命K2與爲質子幫浦阻斷劑 之泰克胃通之配合，鈣離子擷抗劑與ACE阻礙劑之配合， 易寧神注射液與易寧優錠之配合，維他命E與維他命C之配 合，維他命A與維他命C之配合，硬酯酸抗壞血酯與抗壞血 酸及磷酸硬酯醇鎂，輔酶Q10與磷酸硬酯酸醇鎂之配合， 克炎栓劑與抑疼炎栓劑之配合。然而根據以往的方式使用 液劑的形式進行配合時，無論水溶性溶媒或脂溶性溶媒， 其中之一藥物出現沉澱、浮游、或形成凝集塊，抑或與製 劑添加劑配合時引起變化等，無法開發出高含量均一性之 製劑。而本方法可將其中一成分之表面或二種成分之表面 ，藉由以界面活性劑進行包覆製成藥物-界面活性劑複合 體，而使該等成分可進行配合而製成一劑型化。 【實施方式】 -23- 201113049 i.引言 本發明係藉由因應目的，分別將顯示相異物性之複數 種藥物（以下包含化合物或物質），製造內包於s/w、S/0 或S/0/W等界面活性劑之藥物-界面活性劑複合體，計畫 使表面物性改變爲親水性或疏水性而製成一劑型化之技術 。並藉此提高化學性及物理性的安定性，及增加吸收性， 進而可計畫增強藥理效果及減輕副作用。另外，亦可改善 改良苦味及澀味或臭味等。本發明係於一劑型中含有2種 以上且物性相異之藥物，其中1種以上之藥物爲藥物-界 面活性劑複合體，可提供醫藥品或醫療輔助製品者。 另外，本發明係藉由製作將藥物內包於界面活性劑之 藥物-界面活性劑複合體，使藥物的物性均一化，可被微 分散於親水性或脂溶性溶媒中，進而計畫安定性，及提高 吸收性，且掩蔽苦澀味或臭味等，甚或於同一種分散溶媒 (例如水性溶媒或脂溶性溶媒），可提供物性相異之藥物 ，或配合2種以上之藥物-複合體之醫藥品製劑及醫療輔 助製品等，本發明可提供含有藥物-界面活性劑複合體之 製品。 將水溶性藥物分散於脂溶性溶媒時，製造將水溶性藥 物以疏水性界面活性劑進行奈米包覆而使表面爲脂溶性之 s (以下稱作疏水型S或LipoS )。或將該LipoS分散於脂溶 性溶媒中，製造S/0。如此，將水溶性藥物的表面物性變 更爲脂溶性後之LipoS或S/0 ’分散於脂溶性溶媒中’可與 脂溶性藥物一同配合使用。 -24- 201113049 進而將2種水溶性藥物溶解或分散於水溶性溶媒（亦 稱作親水性溶媒）中時，可使該2種藥物在不會因接觸而 引起反應之狀態下，進行溶解或分散。例如將其中一種水 溶性藥物製爲如前述之LipoS，再製爲S/Ο，可製造微小分 散於親水性溶媒中之S/0/W，而可防止於水溶性溶媒中與 其他水溶性藥物接觸。 另外，將疏水性難溶性藥物分散於親水性溶媒中時， 可以親水性界面活性劑對難溶性藥物進行奈米包覆，製造 表面爲親水性之S (以下亦稱作親水型S或Hydros )。可將 該Hydros分散於親水性溶媒中製造S/W。 進而針對親水性的難溶性藥物，可以疏水性界面活性 劑對藥物進行奈米包覆，製造表面爲脂溶性之S(以下亦 稱作疏水型S或LipoS )。另外可將該LipoS分散於脂溶性 溶媒中製造S/Ο。再將該LipoS或S/O分散於脂溶性溶媒中 ，可與其他脂溶性藥物一同配合使用。 親水性溶媒包含親水性凝膠及親水性凝膠基材，但可 藉由進行凝膠化而改變物性，不僅Hydros，亦可使LipoS 分散於親水性凝膠中》 於本說明書中，將「分散」使用爲亦包含「溶解」之意 思。 2.藥物 前述之藥物係可舉出醫藥品、醫療輔助製品、營養因 子及製劑添加劑。醫藥品因係具有藥理學活性，爲具有治 -25- 201113049 療性、診斷性或預防性活性之物質。具體而言可舉出抗生 素、抗病毒劑、麻醉藥、類固醇劑、抗發炎藥、抗腫瘤藥 、抗原、疫苗、抗體、去淤血藥、抗高血壓藥、鎭靜劑、 避孕藥、助孕藥、抗覆交感神經作用劑、鎭痛藥、抗憂鬱 藥、抗精神疾病用藥、利尿劑、心血管作用藥、血管作用 藥、非類固醇性抗發炎藥、營養劑等。例如可舉出熱威樂 素等抗病毒藥物，富眼能、地塞美松、去氫可體醇錠等類 固醇類藥物，或克炎栓劑及抑疼炎栓劑等非類固醇性抗發 炎藥，吉膚黴素'冠達悅歐樂錠、尼卡平錠等抗高血壓藥 ，太平洋紫杉醇、阿黴素、剋癌易、道諾霉素、滅殺除癌 錠、排多癌注射液、喜樹鹼、紫杉醇、敏克瘤注射液及其 衍生物等之抗腫瘤藥，毅力黴素、紅黴素、開羅理黴素等 巨環類抗生素，兩性黴素、艾妥可那唑、咪康哇等抗真菌 藥，二氫基女性素、睪九酮、黃體素己烯雌酚、其衍生物 、生長荷爾蒙、胰島素等荷爾蒙，普達錠等前列腺素系、 環前列腺素系之藥物，維他命D及雙磷酸鹽類、降血鈣素 等反轉骨代謝作用藥，G-CSF及紅血球生成素等作用於血 液系之治療藥’環孢靈及FK5 06等免疫調整劑，奧美拉唑 及舒可來錠等胃腸功能藥等。進而可舉出例如頻尿之治療 用藥、止吐劑、偏頭痛藥、抗癡呆症藥、巴金森氏症治療 藥、高血脂症治療藥、氣喘藥物、異位性皮膚炎治療藥、 乾癖治療藥、抗風濕症藥、白斑病治療藥、阻止迫切性流 產藥等各種藥劑。更進一步的分類可舉出低分子、有機金 屬化合物、糖類、核酸、蛋白質、生肽、金屬、免疫學上 -26- 201113049 的因子等醫藥品。 另外醫療輔助製品可選自胺基酸、含維他命之輔酵素 、礦物質、脂質或糖。 進而，營養因子可選自胺基酸、含維他命之輔酵素、 礦物質、脂質或糖。前述之胺基酸可舉出例如離胺酸、精 胺酸、組胺酸、羥丁胺酸、穀胺基酸、天門冬胺酸、天門 冬醯胺等具極性之胺基酸，甘胺酸、丙胺酸、穀氨醯胺、 胱胺酸、牛磺酸、脯胺酸、絲胺酸等中性胺基酸’纈胺酸 、白胺酸、異白胺酸、甲硫胺酸、苯丙胺酸、色胺酸、胱 胺酸、酪胺酸等疏水性胺基酸及其衍生物。亦包含二生肽 及三生肽等胺基酸衍生物。前述之維他命可舉出維他命B1 、B2、B5、B6、B12、菸鹼酸、維他命C、葉酸、生物素 、肉鹼等水溶性維他命，維他命A、D、K及E等脂溶性維 他命及其衍生物。進而亦包含泛醌等輔酵素類。上述之礦 物質可舉出鈣、鐵、磷、鎂、鈉、鉀、銅、碘、錳、硒、 鋅、鉻、鉬等。前述之脂質可舉出脂肪（中性脂肪）•蠟 等單純脂質，糖脂質•磷脂質等複合脂質及其衍生物。進 而脂質亦可舉出自動物或植物中所萃取之脂質成分。例如 可舉出各種多酚、種子油萃取成分、芝麻類、二十碳五烯 酸類、蜂膠等。上述之糖質可舉出葡萄糖、果糖等單糖， 蔗糖及麥芽糖等雙糖’澱粉及肝糖等多糖類及其衍生物。 另外製劑添加劑可舉出安定化劑、抗氧化劑、著色劑 、防腐劑、保存劑、無痛化劑、香料或緩衝劑等。具體可 舉出、亞硫酸鈉、安息香酸鈉、EDTA4鈉、氯化苯二甲烴 -27- 201113049 銨、己二烯酸、甘草酸二鈉、甘草酸、水楊酸鈉、二丁基 羥基甲苯、硫琥珀酸鈉、三羥甲基甲胺、菸鹼胺、羥基苯 甲酸類、肝素鈉、葡甲胺、糖精、丁烯醯苯胺、尿囊素、 玻尿酸鈉、二甲基聚矽氧烷、茴香油、肉桂油、薄荷油、 香草醛、葉綠素銅鈉、環糊精、三聚氰胺、植酸、阿魏酸 、胺基安息香酸乙酯、肌醇、鹽酸利多卡因、肌酸酐、己 二酸、尿素等。 上述藥物可根據對水的親和性分類爲水溶性與難溶性 3.難溶性 藥物之水溶性與難溶性分類係揭示於BCS ( Biopharmaceutical Classification System) 。BCS係由美國 FDA定義爲下述指引。201113049 VI. Description of the Invention: [Technical Field] The present invention relates to dispersing nanoparticles in the same dispersion medium by adding a water-soluble drug and a poorly soluble drug, and a formulation additive having various physical properties and an oxidizing agent. Among them, a technique in which two or more kinds of drugs and preparation additives having different physical properties are combined in a single preparation are used. [Prior Art] In the treatment, it is rather rare to administer the drug in a single dose. It is better to say that most of the conditions are in the treatment stage, and it is quite common to administer a plurality of therapeutic drugs in combination. Taking surgery as an example, in the preoperative, intraoperative, and postoperative stages, for early recovery and prevention of shock, for the purpose of preventing infection, when injecting sugar and amino acid infusion into the intravenous tube, most of them are injected by the side tube. Antibiotics, etc. When the drip or side tube injection is performed, the pharmaceutical product must be solubilized, and it can be said that it is desired to be soluble in the neutral range. The insoluble drug can not only be administered, or even a soluble drug, it cannot be dissolved in the neutral range. The drug, its administration is a very annoying problem in treatment. The drug is not dissolved in the vicinity of the neutral range, and there are many poorly soluble drugs as described above. Since it is very difficult to mix the drugs with the injection, it is a water-soluble drug that exhibits foreign matter and poor solubility. The drug is dissolved in water, and only a surfactant is added, which is used as an emulsion of the emulsion. However, the emulsion is not only damaged by the expansion of heat, but it will be separated into two layers of precipitate and clear liquid for a long time, which is very difficult to adjust -5-201113049. The most understandable examples of the drug that is so cautiously present are the nutritional factors widely used from pharmaceuticals, foods, and cosmetics. For example, coenzyme vitamins, there are water-soluble vitamins such as vitamin B, which is known as the cause of beriberi, vitamin C, and the cause of scurvy. Vitamin A, which causes night blindness, vitamin D, which promotes calcium absorption, and Insoluble (fat-soluble) vitamins such as vitamin E with vasodilating action. Similarly, of the 20 amino acids necessary for the human body, 8 are hydrophobic amino acids, others are hydrophilic amino acids. Especially for the nine amino acids that cannot be synthesized by the human body, in addition to hydrophilic lysine, succinic acid, histidine, lysine, leucine, isoleucine, methionine, amphetamine Six kinds of amino acids such as acid and tryptophan are hydrophobic, and it is clear that among the same trophic factors, there are two kinds of foreign substances. In this way, in the "drug" containing medical auxiliary products such as nutritional factors, there are two kinds of drugs that are water-soluble and poorly soluble in the use of injections, infusions, internal liquids, lotions, and loach. The formulation of the liquid preparation such as the agent, the paste, and the water-soluble base, or the preparation of the oily injection, the oily capsule preparation, the oily external preparation, and the plaster preparation cause a great problem. For example, an external preparation such as an emulsion, a lozenge, a paste, an oily external preparation, or a plaster preparation is applied to the skin or applied to the skin. When these preparations are prepared, it has not been possible to prepare a preparation having a different physical property in a form which can exhibit the function of the drug. In other words, the skin is the largest barrier of the -6-201113049 object, the extremely hydrophobic structure, the fact that no water-soluble pharmaceuticals have been developed so far, or it has been used as an external preparation such as water-soluble vitamins for medical auxiliary products. It can be fully understood, that is, since the epidermal cells of human skin are metabolized by keratinocytes to physiologically regenerated tissues of keratin in a 28-day cycle, as long as the epidermal tissue is supplied with essential nutrient conditions irrespective of age, culture can be carried out. The epidermal cells are proliferated, and the human skin tissue should be regenerated into normal skin as long as it can receive sufficient nutrient supply from the blood. However, it cannot be provided at the medical site to provide functions such as water-soluble vitamins. The topical topical agent is a variety of skin diseases that can be found starting from atopic dermatitis and dryness. There are various reasons for skin dystrophies. For example, it is generally believed that skin hypotrophy due to hypotension and microvascular ischemic state, normal skin tissue regeneration, and differences in the differentiation speed of the stratum corneum and epidermal cell layers are not observed. In order to improve this phenomenon, in order to improve this phenomenon, only blood flow is increased by a vasodilator, or a therapeutic agent containing the same effect and containing a fat-soluble vitamin E is applied to the skin. In fact, if transdermal administration of trophic factors directly to the skin tissue via the stratum corneum is achieved, it is very gratifying, but the skin tissue is originally a hydrophobic barrier, unable to absorb water-soluble vitamins and amino acids, etc. A soluble (fat-soluble) vitamin external preparation. Therefore, nutrients such as water-soluble vitamins and amino acids necessary for supplying skin tissue, that is, pharmaceutical trophic factors, can be used only in external preparations by changing the use of derivatives having high fat solubility, or for oral administration. Intake method of administration. It has long been hoped that there will be no bio-degradation of water-soluble vitamins 201113049, but the transformation of its surface properties into fat-soluble, fat-soluble vitamins in a dosage form of oily base. On the other hand, when a nutrient factor such as a coenzyme containing a vitamin and an amino acid is produced, the water-soluble and poorly soluble physical properties, stability, taste, and odor are problems in the development of preparations and products. A vitamin-containing enzyme is an enzyme that is essential for the activity of an enzyme in a living organism. The deficiency is due to the insufficiency of the metabolic system associated with the enzyme that utilizes the coenzyme. Vitamins can be classified as water-soluble, water-soluble and fat-soluble fat-soluble. Water-soluble vitamins have vitamin B group (Bl, B2, B3, B5, B6, B7, B9, B12) and vitamin C» fat-soluble vitamins with vitamin A, vitamin D, vitamin E and vitamin K. Vitamin B1 is also known as thiamine, B2 is riboflavin, B3 is nicotinic acid, B5 is pantothenic acid, B6 is anti-dermatitis, B 7 is biotin, B 9 is folic acid, and B 1 2 is cyanide Amine, vitamin C is also known as ascorbic acid. In addition to the above vitamins, the vitamins of the vitamins contain various vitamin derivatives and coenzymes. There are various types of carotenoids in vitamin A, various calcified steroids in vitamin D, various tocopherols in vitamin E, and various naphthoquinone derivatives in vitamin K. Other coenzymes other than vitamins include water-soluble orotic acid, pantothenic acid, amygdalin, antiulcer, and carnitine. Examples of the fat-soluble coenzyme include essential fatty acids such as linoleic acid, quercetin, and ubiquinone. Ubiquinone is also known as coenzyme Q10 (CoQlO). Amino acids, minerals, and sugars are classified as water-soluble nutrient factors. In addition, lipids are classified as fat-soluble trophic factors. The lipids include various -8-201113049 polyphenols, seed oil extract components, sesame seeds, eicosapentaenoic acid, propolis, and the like. Thus, in the case of a nutrient factor, both water-soluble and fat-soluble ones are preferred, and it is preferred to use these components in combination for the purpose of use. When preparing injections, infusions, internal liquids, eye drops, nose drops, or aqueous lotions, the water-soluble components are directly dissolved in the water-soluble base for two or more components having different physical properties, and the solubility is poor. The composition changes its surface properties to be hydrophilic, and is compounded into a dosage form in the form of a drug-surfactant complex. Among the two components which are mixed in a water-soluble solvent to produce a change in water solubility, one of them is a hydrophilic drug-surfactant complex, thereby preventing direct contact between the two components and preventing the change in the compounding. [Patent Document 1] [Patent Document 1] JP-A-2004-433 55 [Patent Document 2] International Publication No. WO2005/0 94789 [Patent Document 3] International Publication No. WO2006/0 25583 [Patent Document 4] Open 2004-8837 [Non-Patent Document] [Non-Patent Document 1] Japanese Pharmacol. (Folia Pharmacol. Jpn. 127;213-216 (2006) [Non-Patent Document 2] Summary of the 36th SPG Forum Speech, 50-53 (2001) [Non-Patent Document 3] International Journal of Pharmaceutics -9 - 201113049 252; 271- 274 (2003) [Non-Patent Document 4] International Journal of Pharmaceutics 3 3 8; 1 74- 1 79 (2007) [Non-Patent Document 5] Pharmaceutical Development and Technology 12; 321-325 (2007) [Summary of Invention] [Invention The problem to be solved] It is used in pharmaceuticals, medicines, foods, and cosmetics as a nutritional supplement. It is divided into water-soluble and poorly soluble, but water-soluble substances are dispersed. It is very difficult to dissolve an oily preparation of a poorly soluble substance. Similarly, it is very difficult to uniformly disperse and mix a poorly soluble substance in an aqueous injection preparation, an internal liquid preparation, or the like which is composed of a water-soluble substance. Further, "drugs", that is, pharmaceuticals, medical auxiliary products, and the like, are difficult to make a plurality of drugs to be blended in the same dispersion medium because the preparation additives for manufacturing them are water-soluble or poorly soluble. The present invention is intended to uniformize the physical properties of a plurality of drugs which are intended to be combined, and to focus on dispersing and mixing at least two or more kinds of drugs having different physical properties in the same solvent, thereby suppressing changes in the compounding and improving One of a plurality of drugs that exhibit stability and increase absorption to living organisms, and suppress side effects, and which are intended to mask bitterness or odor, and which exhibit water-soluble or poorly soluble foreign substances. Or both of them can be made into a drug-surfactant complex containing S/W, S/Ο or S/0/W surfactant, and manufactured and supplied with nanometer in response to the purpose of the preparation of -10-201113049 A pharmaceutical product, or a medical auxiliary product, dispersed in a dispersion medium of any of a water-soluble base or an oily base. In particular, it is a pharmaceutical or medical auxiliary product containing a water-soluble vitamin and an amino acid, and since it does not have transdermal absorbability, the hydrophilic drug or the medical auxiliary product is coated with a surfactant, and the drug is used. - The form of the surfactant complex changes its physical properties to fat solubility, and can be used to stabilize the drug and improve the transdermal absorbability, and it is expected that more than one type of fat-soluble drug or medical auxiliary product material can be added. The pharmaceutical preparation of the compounding agent and the development of the medical auxiliary product can be used as an oily preparation. For example, it is currently desired to change the surface of water-soluble vitamin C to fat-soluble, and then mix it with fat-soluble vitamin E to prepare a one-form oily preparation. The surface of the water-soluble vitamin C is changed to fat-soluble, and the surface of the water-soluble hydroxyproline is converted into fat-soluble, and the oily preparation is prepared as a one-part type by blending the two, and is expected to be on the skin. It has a multiplicative effect and can be expected to restore skin vitality and wound healing effects. These problems have been solved by the present invention. Further, by manufacturing a poorly soluble drug into a drug-surfactant complex coated with a hydrophilic surfactant, it is desirable to produce an injection, an infusion solution, an internal solution, a water-soluble gel internal preparation, or a topical gel cream. And a lotion, an electrical induction liquid agent, and a gelling agent using an anionic high hydrophilic surfactant. For example, it is desirable to change the surface of the coenzyme Q to be hydrophilic, and to prepare a gel internal solution dissolved in a water-soluble gel. Further, it is also desired to produce a preparation which is dissolved in an aqueous electrode solution for ion electrophoresis to revitalize the skin. These problems have been solved by the present invention. -11 - 201113049 In response to the purpose, by changing the surface of the drug to hydrophilicity and fat solubility, the surface properties of a plurality of drugs can be made uniform, and any preparation of water-soluble or fat-soluble can be produced. It is not only expected to be soluble in a water-soluble solvent but also ionized by making the drug hydrophilic. In addition, since two or more kinds of drugs having different physical properties can be stably formulated in any of the dispersion media, it is possible to prevent the content unevenness which is observed when the suspension powder is formulated, and the heat treatment step and the change with time. The resulting settling and phase separation. Further, by using the present technology, it is possible to prevent the change of the compound from being prevented by directly contacting the drug which causes the compounding change. Examples of the change include, for example, an addition reaction of vitamin C with sodium bisulfite, an amine acid, an amine-containing drug and a saccharide, an amine carbonyl reaction of an aldehyde-containing drug, a sulfate-containing compound, and a precipitation of an amine-based drug. Reaction, terbinafine hydrochloride and chlorodimethylammonium chloride. Others may be combined with the changes of polyethylene glycol and phenobarbital, polyethylene glycol and vinca alkaloids, the combination of dibutylhydroxytoluene and amine compounds, aminophenanthine and glucose Schiff base, tetracycline reacts with furfural of an alkaline earth metal, adrenaline is racemized by sulfite group, benzoic acid is formed with acidic amine, methicillin and phenancillin The complex is formed, the adiponectin reaction between aspirin and phenylephrine, and the same heterogeneity of the same synthetic vitamin. Techniques for overcoming these issues are currently being sought. In the present method, the surface of one of the components or the surface of the two components can be made into a drug-surfactant complex by coating with an interfacial surfactant, and the compounding change can be suppressed. The poorly soluble drug and the water-soluble drug, the poorly soluble drug and the poorly soluble drug -12-201113049, the water-soluble drug and the water-soluble drug are combined into one dosage form, and the effect of improving the drug effect of each other and suppressing the side effect is hyperlipemia treatment. The combination of eicosapentaenoic acid and Lipitor, vitamin K2 and the combination of the proton pump blocker Tektronix, calcium ion antagonist and ACE inhibitor, Yi Ning Shen injection and The combination of Yi Ning and Ingot, the combination of vitamin E and vitamin C. The combination of vitamin A and vitamin C, ascorbyl stearate and ascorbic acid and magnesium citrate, coenzyme Q10 and magnesium stearate , Keyan suppository and anti-pain suppository. However, when a compounding agent is used in the form of a liquid agent according to the conventional method, it is impossible to develop a drug which precipitates, floats, or forms agglomerates, or changes with a formulation additive, regardless of a water-soluble solvent or a fat-soluble solvent. High content uniformity preparation. In the present method, the surface of one of the components or the surface of the two components can be made into a drug-surfactant composite by coating with a surfactant, and the components can be compounded to form a dosage form. . [Means for Solving the Problem] In order to solve the related problems, a drug-surfactant complex in which a drug is encapsulated in a surfactant is produced, and it is made into a S/ which can be minutely dispersed in a hydrophilic solvent in accordance with the purpose. W, or S/0 which can be dispersed in a fat-soluble solvent, and further can be dispersed in a S/0/W preparation and product of a hydrophilic solvent, and a plurality of drugs can be blended in the same dispersion medium (hydrophilic solvent, water-soluble) In a solvent and a fat-soluble solvent). That is, the present invention is as follows. (1) A preparation for dissolving or dispersing a water-soluble drug and a poorly soluble drug dissolved in any one of a solvent selected from a hydrophilic solvent or a fat-soluble solvent, (2) as described in the above item (1) The preparation, wherein the water-soluble drug and the poorly soluble drug are respectively selected from the group consisting of a pharmaceutical, a nutritional factor, a formulation additive, and any combination thereof. (3) The preparation according to (1) or (2), wherein the poorly soluble drug, for pH 1. 0~7. The solubility of 25 ml of 0 ml buffer is the solubility below the maximum drug content contained in 1 unit of the preparation, which is equivalent to the Low Solubility (LS) of BCS (Biopharmaceutical Classification System, Principle of Drug Solubility and Penetration). (4) The preparation according to (1), wherein the water-soluble drug or the poorly soluble drug is a drug-surfactant complex (hereinafter abbreviated as Solid or S) which is contained in a solid state. (5) The preparation according to any one of the above (1) to (4) wherein the poorly soluble drug is a hydrophobic poorly soluble drug, and the poorly soluble drug is a drug-surfactant complex (Solid) dispersed in the aqueous phase (Water) Solid-in-Water (S/W) type. (6) The preparation according to any one of (1) to (4), wherein the water-soluble drug-drug-surfactant complex (Solid) is dispersed in the oil-based Solid-in-Oil (S/ O) type. (7) The preparation according to any one of (1) to (4), wherein the poorly soluble drug is a hydrophilic poorly soluble drug, and the poorly soluble drug is a drug-surfactant complex (Solid) dispersed in the oil phase ( Oil) s〇lid-in-0il (S/0) type. The preparation of any one of (1) to (4), wherein the water-soluble drug-drug-surfactant complex (Solid) is dispersed in the oil phase (Sol id-in-) The oil (S/0) type, which in turn disperses the oil phase in the aqueous phase, is in the form of Solid-in-Oil-in-Water (S/0/W). (9) The preparation according to any one of (1) to (4), wherein the poorly soluble drug is a hydrophilic poorly soluble drug, and the poorly soluble drug is a drug-surfactant complex (Solid) dispersed in the oil phase ( Oil), and then the oil phase is dispersed in the water phase, which is Solid-in-Oil-in-Water (S/0/W) type 〇(1 0 ) as in any one of items (1) to (4) The preparation of the invention, wherein the water-soluble drug is dissolved in a hydrophilic solvent, the poorly soluble drug is a hydrophobic poorly soluble drug, and the hydrophobic poorly soluble drug is dispersed in the aqueous phase by a drug-surfactant complex (Solid) The form of Solid-in-Water (S/W) of (Water) is dispersed in a hydrophilic solvent. (11) The preparation according to any one of (1) to (4), wherein the water-soluble drug is dispersed in the oil phase (Oil) of Solid-in-Oil (S) by a drug-surfactant complex (Solid) The type of /Ο) is dispersed in a lipid solvent, and the poorly soluble drug is a hydrophobic poorly soluble drug and is dissolved in a fat vehicle. (12) The preparation according to any one of (1) to (4), wherein the water-soluble drug is dispersed in the oil phase (Oil) of Solid-iii-Oil (Sil) by a drug-surfactant complex (Solid) /Ο), and then dispersed in the aqueous phase of Solid-in-〇il-in-Water (S/0/W), dispersed in a hydrophilic solvent, the poorly soluble drug is a hydrophobic poorly soluble drug, And the hydrophobicity is difficult -15-201113049 The soluble drug is dispersed or dispersed in the Sol id-in-Water (S/W) form of the aqueous phase (Solid), and is dispersed. In a hydrophilic solvent. (1) The preparation according to any one of (1) to (4), wherein the water-soluble drug is dispersed in the oil phase (Oil) of Solid-in-Oil (Solid) by a drug-surfactant complex (Solid) The type of S/0) is dispersed in a fat-soluble solvent, the poorly soluble drug is a hydrophilic poorly soluble drug, and the drug-surfactant complex (Solid) is dispersed in the oil phase (Oil) Solid-in- The type of Oil (S/O) is dispersed in a fat-soluble solvent. (14) The preparation according to any one of (1) to (4), wherein the water-soluble drug is dissolved in a hydrophilic solvent, and the hydrophilic poorly soluble drug is dispersed by a drug-surfactant complex (Solid) In the oil phase (Oil) Solid-in-Oil (S/0), and then dispersed in the water phase of the 8〇1丨 (1411-Oil-in-Water (S/0/W) type, The preparation of any one of (1) to (4), wherein the water-soluble drug is dispersed in the aqueous gel, and the poorly soluble drug is a hydrophilic poorly soluble drug, The drug-surfactant complex (Solid) is dispersed in the form of Solid-in-Water (S/W) of the water phase and is dispersed in the aqueous gel. (16) such as (1) to (1) The preparation according to any one of the preceding claims, wherein the medicament is selected from the group consisting of pharmaceuticals having pharmacologically active, therapeutic, diagnostic, or prophylactic active substances. (1 7 ) as in items (1) to (1 5) A preparation according to any one of the preceding claims, wherein the medicament is selected from the group consisting of amino acids, coenzymes containing vitamins, minerals, lipids or nutrients of sugars of 16-201113049. (1 8 ) as (1) to (1 5) Nine a preparation, wherein the drug is selected from the group consisting of stabilizers, antioxidants, colorants, preservatives, preservatives, painless agents, buffers, amino acids, coenzymes containing vitamins, minerals, lipids or sugars. (1 9 ) A method for producing a compounding agent, which is characterized in that a hydrophobic poorly soluble drug and a S/O (Solid-in-Oil) water-soluble drug are dispersed in a fat-soluble solvent. 20) A method for producing a compounding agent characterized in that a water-soluble drug and a solid-in-water (S/W) hydrophobic poorly soluble drug are uniformly dispersed in a hydrophilic solvent. (21) The preparation method of the compounding agent is characterized in that the water-soluble drug of S〇nd_in-Oil-in-Water (S/0/W) and the hydrophobicity of s〇lid-in-Water (S/W) The poorly soluble drug is uniformly dispersed in the hydrophilic solvent. (22) A method for producing a compounding agent characterized by S/O (Solid-in-Oil) water-soluble drug, and S/O ( Solid-in-Oil) The hydrophilic poorly soluble drug is uniformly dispersed in a fat-soluble solvent. (23) A method for producing a compounding agent, The system can uniformly disperse the water-soluble drug and the solid-in-Oil-in-Water (S/0/W) hydrophilic poorly soluble drug in the hydrophilic solvent. (24) Manufacture of a compounding agent The method is characterized in that a water-soluble drug and a solid-in-water (S/W) hydrophilic poorly soluble drug are uniformly dispersed in a hydrophilic solvent. -17- 201113049 (25) A product containing a drug-surfactant complex, which comprises a drug made by a water-soluble drug and a poorly soluble drug S/W (Solid-in-Water)- An aqueous electrode solution for iontophoresis of a surfactant complex is used as an aqueous solution containing a drug for iontophoresis. (26) A pharmaceutical product characterized by containing the preparation according to any one of (1) to (18). (27) A food product characterized by comprising the preparation according to any one of (1) to (18). (2) A cosmetic comprising the preparation according to any one of (1) to (18). (29) A preparation characterized by dispersing a water-soluble drug S/0, uniformly dispersing it in a fat and oil together with a hydrophobic poorly soluble drug, and molding it in a soft capsule or a hard capsule. (30) A fat-soluble solvent characterized in that a water-soluble drug is S/O-formed and uniformly dispersed in a fat-soluble solvent, and further, a S/0-reactive hydrophilic poorly soluble drug or a hydrophobic poorly soluble drug Suspended or dispersed in a fat-soluble solvent. (31) A preparation characterized by molding a fat-soluble solvent as in (29) to (30), in a soft capsule or a hard capsule. (3 2 ) An article characterized in that a preparation formed by filling a soft capsule or a hard capsule as in (3 1 ) is packaged in a tear-wrapped or extruded type of bubble wrap. (33) A preparation characterized in that a drug-surfactant complex (hereinafter referred to as Solid or S) in which a water-soluble drug and/or a poorly soluble drug is encapsulated in a solid state is uniformly dispersed in In the aqueous gelling agent, it is molded into a quantitative container. (34) A preparation characterized by a plurality of drugs which cannot coexist in a single solvent, each of which is made into a drug-surfactant complex so as to be dispersible in the solvent. (35) The preparation of (34), wherein the plurality of drugs are water-soluble drugs, each drug is prepared as a drug-surfactant complex (LipoS) dispersed in an oil phase (Oil), to Solid The type of -in-Oil (S/O) is dispersed in a fat-soluble solvent. (36) The preparation according to (34), wherein the plurality of drugs are water-soluble drugs, and each drug is prepared as a drug-surfactant complex (LipoS) dispersed in the oil phase (Oil) Solid-in -Oil (S/0), which is further dispersed in a hydrophilic solvent in a form of Sol id-in-Oil-in-Water (S/0/W) dispersed in an aqueous phase. (37) The preparation of (34), wherein the plurality of drugs are hydrophobic poorly soluble drugs, and each drug is prepared as a drug-surfactant complex (Hydros) dispersed in a water phase (Water). It is dispersed in a hydrophilic solvent in the form of Solid-in-Water (S/W). (38) The preparation of (34), wherein the plurality of drugs are hydrophilic poorly soluble drugs, and each drug is prepared as a drug-surfactant complex (LipoS) dispersed in the oil phase (Oil) of Solid -in-Oil (S/0), and then in the form of 3〇1丨(1-丨11-0丨1-丨11-1^3161' (3/0/ rating) dispersed in the water phase, Disperse in a hydrophilic solvent. (39) The preparation according to (34), wherein the plurality of drugs are all -19-201113049 hydrophilic poorly soluble drugs, and each drug is made into a drug-surfactant complex ( Solid) is dispersed in an aqueous gel in a form of Solid-in-Water (S/W) dispersed in a water phase. (40) Any one of (34) to (39) The preparation, wherein the plurality of drugs are a drug which causes a chemical reaction in a solvent, the drug of any one of (34) to (39), wherein the plurality of drugs comprise an oxidizing drug and The preparation of any one of (3) to (3), wherein the plurality of drugs comprise a metal ion-containing drug and a drug-forming compound (43) A method for producing a preparation comprising a plurality of drugs which cannot coexist in a single solvent, each of which is prepared as a drug-surfactant complex, and the drug-surfactant complex is dispersed in a solvent. (44) The method for producing a preparation according to the item (43), wherein the plurality of the drugs are water-soluble drugs, each of which is a drug-surfactant complex (LipoS) to be dispersed in the oil phase (Oil) a solid-in-Oil (S/0) type, dispersed in a fat-soluble solvent, (45) a method of producing a preparation according to (43), wherein the plurality of drugs are water-soluble drugs, Each drug is prepared as a drug-surfactant complex (LipoS) dispersed in the oil phase (Oil) of Solid-in-Oil (S/Ο), and then dispersed in the aqueous phase of Solid-in-Oil-in- The water (S/0/W) type is dispersed in a hydrophilic solvent. -20- 201113049 (46) The preparation method of the preparation according to the item (43), wherein the plurality of drugs are hydrophobic poorly soluble drugs Dissolving each drug as a drug-surfactant complex (Hydros) in the aqueous phase (Water), The solid-in-water (S/W) type is dispersed in a hydrophilic solvent. (47) The method for producing a preparation according to the item (43), wherein the plurality of drugs are hydrophilic poorly soluble drugs, Each drug is prepared as a drug-surfactant complex (LipoS) dispersed in the oil phase (Oil) of Solid-in-〇il (S/O), and further dispersed in the aqueous phase of Solid-in-Oil-in- Water ( s / 0 / w) type, dispersed in a hydrophilic solvent. (48) A method of producing a preparation according to any one of (43) to (47), wherein the plurality of drugs are drugs which cause a chemical reaction in a solvent. (49) A method of producing a preparation according to any one of (43) to (47), wherein the plurality of drugs comprise a drug having an oxidizing action and a drug having a reducing action. (50) A method of producing a preparation according to any one of (43) to (47), wherein the plurality of drugs are a drug containing a metal ion and a drug forming a complex. (51) A method of masking or deodorizing a drug, characterized in that the drug is dispersed in a form of a drug-surfactant complex in a solvent. (52) A method for stabilizing a drug, characterized in that the drug is dispersed into a solvent in a form of a drug-surfactant complex. Effect of the Invention The present invention is made by encapsulating a drug in an interface. Active Agent Drug - 21 - 201113049 Surfactant Complex, which makes the drug's physical properties uniform, can be slightly dispersed in hydrophilic or fat-soluble solvent, and thus can be considered to improve stability and absorbability, and can mask bitter taste Or a odor or the like, and a drug-interface can be provided in the same dispersion solvent, a drug having a different physical property, or a pharmaceutical preparation or a medical auxiliary product which can be combined with two or more drug-surfactant complexes. A product of an active agent complex. According to the present invention, the physical properties of the drug exhibiting the foreign matter property can be made uniform, stable and absorbable, and the bitterness, bitterness or odor can be improved. Further, depending on the purpose, by changing the surface of the drug to hydrophilicity and fat solubility, the surface properties of a plurality of drugs can be made uniform, and any preparation of water-soluble or fat-soluble can be produced. By making the drug hydrophilic, it is not only expected to be soluble in a water-soluble solvent, but also ionized. In addition, since two or more kinds of drugs having different physical properties can be stably formulated in any of the dispersion media, it is possible to prevent the content unevenness which is observed when the suspension powder is formulated, and the heat treatment step and the change with time. The resulting settling and phase separation. Further, by using the present technology, it is possible to prevent the change of the compound from being prevented by directly contacting the drug which causes the compounding change. Examples of the change include, for example, an addition reaction of vitamin C with sodium bisulfite, an amine acid, an amine-containing drug and a saccharide, an amine carbonyl reaction of an aldehyde-containing drug, a sulfate-containing compound, and a precipitation of an amine-based drug. Reaction, terbinafine hydrochloride and chlorodimethylammonium chloride. Others may be combined with the changes of polyethylene glycol and phenobarbital, polyethylene glycol and vinca alkaloids, the combination of dibutylhydroxytoluene and amine compounds, aminophenanthine and glucose Schiff base, tetracycline and alkaline earth metal furfural-22- 201113049 reaction, adrenaline due to the sulfite group racemic, benzoic acid and citric acid formed acid amine, penicillin The form of benzicillin forms a complex, the adiponectin reaction between aspirin and phenylephrine, and the heterogeneity of the same synthetic vitamin. Techniques for overcoming these issues are currently being sought. In the present method, the surface of one of the components or the surface of the two components can be made into a drug-surfactant complex by coating with a surfactant, and the compounding change can be suppressed. The poorly soluble drug and water are dissolved. A drug, a poorly soluble drug, a poorly soluble drug, a water-soluble drug, and a water-soluble drug are combined into one dosage form, and the effect of improving the effect of each other's drugs and suppressing side effects are as follows: eicosapentaenoic acid and Lipu, a therapeutic agent for hyperlipemia Properly cooperate, vitamin K2 is compatible with the proton pump blocker Tektronix, calcium ion antagonist and ACE inhibitor, Yi Ning Shen injection and Yi Ning excellent ingot, vitamin E and vitamin The combination of C, vitamin A and vitamin C, stearic acid ascorbate with ascorbic acid and magnesium citrate, coenzyme Q10 and magnesium stearate, the combination of Keyan suppository and anti-pain suppository . However, when it is blended in the form of a liquid agent according to the conventional method, it is impossible to develop a drug, such as a water-soluble solvent or a fat-soluble solvent, in which one of the drugs precipitates, floats, or forms agglomerates, or changes with the formulation additives. High content uniformity preparation. In the present method, the surface of one of the components or the surface of the two components can be made into a drug-surfactant composite by coating with a surfactant, and the components can be compounded to form a dosage form. . [Embodiment] -23- 201113049 i. INTRODUCTION The present invention provides a drug which is contained in a surfactant such as s/w, S/0 or S/0/W by a plurality of drugs (hereinafter including a compound or a substance) which exhibit different physical properties by means of the purpose. - A surfactant complex, a technique in which the surface properties are changed to hydrophilic or hydrophobic to make a dosage form. In order to improve the chemical and physical stability and increase the absorption, it is planned to enhance the pharmacological effect and reduce side effects. In addition, it can improve the improvement of bitterness, astringency or odor. The present invention is a drug containing two or more kinds of different physical properties in one dosage form, and one or more of the drugs are drug-binder active agent complexes, and can provide pharmaceuticals or medical auxiliary products. In addition, the present invention makes the physical properties of the drug uniform by preparing a drug-surfactant complex in which the drug is encapsulated in a surfactant, and can be microdispersed in a hydrophilic or fat-soluble solvent to further calculate stability. And improving absorption, and masking bitterness or odor, or even the same dispersion solvent (for example, aqueous solvent or fat-soluble solvent), can provide drugs with different physical properties, or can be combined with two or more drugs-complex For pharmaceutical preparations, medical auxiliary products, and the like, the present invention can provide a product containing a drug-surfactant complex. When the water-soluble drug is dispersed in a fat-soluble solvent, a water-soluble drug is coated with a hydrophobic surfactant to form a fat-soluble s (hereinafter referred to as hydrophobic type S or LipoS). Alternatively, the LipoS is dispersed in a fat-soluble solvent to produce S/0. Thus, LipoS or S/0' after the surface property of the water-soluble drug becomes more fat-soluble is dispersed in the fat-soluble solvent, and can be used together with the fat-soluble drug. -24- 201113049 Further, when two kinds of water-soluble drugs are dissolved or dispersed in a water-soluble solvent (also referred to as a hydrophilic solvent), the two drugs can be dissolved without being reacted by contact or dispersion. For example, one of the water-soluble drugs can be made into the above-mentioned LipoS, and then made into S/Ο, which can produce S/0/W which is minutely dispersed in the hydrophilic solvent, and can prevent contact with other water-soluble drugs in the water-soluble solvent. . Further, when the hydrophobic poorly soluble drug is dispersed in a hydrophilic solvent, the hydrophilic surfactant can be coated with a poorly soluble drug to form a hydrophilic S (hereinafter also referred to as hydrophilic S or Hydros). . The Hydros can be dispersed in a hydrophilic solvent to produce S/W. Further, in the case of a hydrophilic poorly soluble drug, the drug may be coated with a hydrophobic surfactant to form a fat-soluble S (hereinafter also referred to as hydrophobic type S or LipoS). Alternatively, the LipoS may be dispersed in a fat-soluble solvent to produce S/Ο. The LipoS or S/O is dispersed in a fat-soluble solvent and can be used together with other fat-soluble drugs. The hydrophilic solvent contains a hydrophilic gel and a hydrophilic gel substrate, but the physical properties can be changed by gelation, and not only Hydros, but also LipoS can be dispersed in the hydrophilic gel. In the present specification, "Distributed" means "dissolved" as well. 2. Drugs The aforementioned drugs are medicinal products, medical auxiliary products, nutrients and preparation additives. A pharmaceutical product has pharmacological activity and is a substance having therapeutic, diagnostic or prophylactic activity of -25-201113049. Specifically, antibiotics, antiviral agents, anesthetics, steroids, anti-inflammatory drugs, antineoplastic agents, antigens, vaccines, antibodies, decongestants, antihypertensive drugs, sedatives, contraceptives, and pregnancy-preventing drugs are mentioned. Medicine, anti-sympathetic sympathetic agent, analgesic, anti-depressant, antipsychotic medication, diuretic, cardiovascular drug, vasoactive drug, non-steroidal anti-inflammatory drug, nutrient, etc. For example, antiviral drugs such as Rexon, steroid drugs such as Fuyan, Dexamethasone, and Dehydrocoholin, or non-steroidal anti-inflammatory drugs such as Keyan suppository and anti-inflammatory suppository, Anti-hypertensive drugs such as ceramin's crown yue yue ingot, nicardin ingot, paclitaxel, doxorubicin, gram cancer, daunorubicin, killing cancer ingots, multi-cancer injection, hi Anticancer drugs such as alkaloids, paclitaxel, Minke tumor injections and their derivatives, giant ring antibiotics such as tetracycline, erythromycin, and cairomycin, amphotericin, icotyconazole, and micon wow Antifungal drugs, dihydro-based females, octadecyl ketones, lutein diethylstilbestrol, its derivatives, growth hormones, insulin and other hormones, prostaglandins such as prolene, prostaglandin drugs, vitamin D and diphosphate Salt, calcitonin and other reversed bone metabolism drugs, G-CSF and erythropoietin and other therapeutic agents such as cyclosporine and FK5 06 acting on the blood system, omeprazole and sulco Intestinal and other gastrointestinal functional drugs. Further, for example, therapeutic drugs for urinary tract, antiemetic agents, migraine drugs, anti-dementia drugs, treatments for Parkinson's disease, therapeutic drugs for hyperlipemia, asthma drugs, therapeutic drugs for atopic dermatitis, and cognac Various drugs such as therapeutic drugs, anti-rheumatic drugs, leukoplakia treatment drugs, and prevention of urgent abortion drugs. Further classifications include pharmaceuticals such as low molecular weight, organic metal compounds, saccharides, nucleic acids, proteins, peptides, metals, and immunological factors -26-201113049. Alternatively, the medical auxiliary product may be selected from the group consisting of amino acids, coenzymes containing vitamins, minerals, lipids or sugars. Further, the trophic factor may be selected from the group consisting of amino acids, coenzymes containing vitamins, minerals, lipids or sugars. The aforementioned amino acid may, for example, be a polar amine such as aminic acid, arginine, histidine, hydroxybutyric acid, glutamine, aspartic acid, aspartame or the like, and a glycine. Neutral amino acids such as acid, alanine, glutamine, cystine, taurine, lysine, and serine, 'valine acid, leucine, isoleucine, methionine, Hydrophobic amino acids such as phenylalanine, tryptophan, cystine, tyrosine and the like. Amino acid derivatives such as dipeptides and tripeptides are also included. The aforementioned vitamins include vitamin B1, B2, B5, B6, B12, niacin, vitamin C, folic acid, biotin, carnitine and other water-soluble vitamins, and fat-soluble vitamins such as vitamins A, D, K and E and derivative. Further, it also includes coenzymes such as ubiquinone. Examples of the minerals mentioned above include calcium, iron, phosphorus, magnesium, sodium, potassium, copper, iodine, manganese, selenium, zinc, chromium, and molybdenum. Examples of the lipids include simple lipids such as fat (neutral fat) and wax, and complex lipids such as sugar lipids and phospholipids and derivatives thereof. Further, the lipid may also be a lipid component extracted from an animal or a plant. For example, various polyphenols, seed oil extract components, sesame seeds, eicosapentaenoic acid, propolis, and the like can be given. Examples of the above-mentioned saccharide include monosaccharides such as glucose and fructose, and polysaccharides such as disaccharide and starch such as sucrose and maltose, and glycosides and derivatives thereof. Further, the formulation additive may, for example, be a stabilizer, an antioxidant, a colorant, a preservative, a preservative, a painless agent, a perfume or a buffer. Specific examples thereof include sodium sulfite, sodium benzoate, sodium EDTA4, chlorobenzene hydrocarbon-27-201113049 ammonium, hexadienoic acid, disodium glycyrrhizinate, glycyrrhizic acid, sodium salicylate, dibutylhydroxytoluene, and sulfur succinic acid. Sodium, trishydroxymethylmethylamine, nicotinamide, hydroxybenzoic acid, sodium heparin, meglumine, saccharin, butenanilide, allantoin, sodium hyaluronate, dimethyl polyoxane, fennel oil, Cinnamon oil, peppermint oil, vanillin, copper chlorophyllin, cyclodextrin, melamine, phytic acid, ferulic acid, ethyl benzoic acid ethyl ester, inositol, lidocaine hydrochloride, creatinine, adipic acid, urea, etc. . The above drugs can be classified into water-soluble and poorly soluble according to their affinity for water. The water-soluble and poorly soluble classification of poorly soluble drugs is disclosed in the BCS (Biopharmaceutical Classification System). BCS is defined by the US FDA as the following guidelines.
Guidance for industry : Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system BCS係藥物對pHl.O〜7.5之25 0ml緩衝液之溶解度顯示 1單位製劑中所含最大藥物含量以上時，分類爲水溶性藥 物，以下時分類爲難溶性藥物。 另外，難溶性藥物可根據親水性與疏水性之平衡，分 類爲親水性難溶性藥物及疏水性難溶性藥物。 4.界面活性劑 -28- 201113049 性於 兩係 、 劑 性 性 子活 離面 陽界 、 各 性 。 子劑 i 4-U 離性 陰活 有面 類界 種等 之劑 劑性 性活 活面 面界 界性 述子 前離 非 分子中具有親水基及疏水基，根據親水基與疏水基之平衡 (HLB値），可被分類爲親水性或疏水性（親油性）。 界面活性劑親水性與疏水性之平衡，係以HLB値（ Hydrophilic Lipophilic Balance)爲指標而表示。HLB 値 採0至20表示，愈接近0者疏水性愈高，愈接近20者表示親 水性愈高。 親水性界面活性劑的HLB値在約8以上時會形成0/W型 乳糜狀，而疏水性界面活性劑的HLB値在未達8時會形成 W/0型乳糜狀。 S / 0用之界面活性劑係疏水性界面活性劑，亦可添加 疏水性界面活性劑一半量以下之親水性界面活性劑，以 10%以下爲佳。 用於將S/Ο化後之油劑再分散於水相所得之S/0/W者， 可於水相中添加親水性界面活性劑而進行調製。此時，無 論於油相或水相中，可添加親水性界面活性劑量之一半的 疏水性界面活性劑，或親水性界面活性劑，以1 0%以下爲 佳》另外亦可於水相中添加疏水性界面活性劑水相中添 加之疏水性界面活性劑爲親水性界面活性劑半量以下，以 10%以下爲佳。 S/W用之界面活性劑係親水性界面活性劑。可添加親 水性界面活性劑半量以下之疏水性界面活性劑，以1 0%以 下爲佳。親水性的界面活性劑可舉出如下所述之陰離子性 -29- 201113049 、陽離子性、兩性、非離子性界面活性劑。 陰離子性界面活性劑可使用脂肪酸性皂、環烷甲酸性 皂、長鏈醇硫酸酯、聚氧乙烯烷基苯基醚硫酸酯鹽、脂肪 酸單甘油酯硫酸酯、脂肪酸單烷基醇胺硫酸酯、鹼性磺酸 鹽、〇：-磺酸化脂肪酸鹽、二烷基磺酸化丁二酸鹽、聚氧 乙烯辛基苯基醚磺酸鹽、烷基苯擴酸鹽、聚氧乙烯烷基苯 基醚磷酸酯鹽、聚氧乙烯烷基醚磷酸酯鹽、月桂基硫酸鈉 等。 陽離子性界面活性劑可使用長鏈一級胺鹽、烷基三甲 基銨鹽、二烷基二甲基銨鹽、烷基嘧啶鹽、聚氧乙烯烷基 胺、烷基咪唑啉等。 兩性界面活性劑可使用Ν -烷基、/3-胺基丙酸鹽、Ν_ 烷基A-亞氨基二丙酸鹽等。 親水性的非離子性界面活性劑可使用高級醇乙烯氧附 加物、院基苯基乙稀氧附加物、脂肪酸乙稀氧附加物、多 元醇脂肪酸酯乙烯氧附加物'高級烷基胺基乙烯氧附加物 、脂肪酸胺基乙烯氧附加物 '油脂之乙烯氧附加物、甘油 脂肪酸酯、季戊四醇之脂肪酸酯、多元醇之院基醚、院基 醇胺類之脂肪酸胺等。 非離子性界面活性劑中，亦可使用例如山梨醇及山梨 醇酐之脂肪酸酯、聚氧乙烯山梨醇酐脂肪酸酯、聚乙嫌乙 二醇脂肪酸酯、蔗糖脂肪酸酯、聚氧乙烯蓖麻油（ polyethoxylatedcastoroil )、聚氧乙烯氫化蓖麻油（ polyethoxylatedhydrogenatedcastoroil)、聚氧乙稀聚丙稀 -30- 201113049 甘油共聚合體、甘油脂肪酸酯、聚甘油脂肪酸酯等。 聚氧乙烯山梨醇酐脂肪酸酯特別以聚山梨醇酐脂肪酸 酯20、40、60、8 0等爲佳。聚乙烯乙二醇脂肪酸酯特別以 單月桂酸聚乙烯甘油醇等爲佳。蔗糖脂肪酸酯特別以蔗糖 棕櫚酸酯類（例如商品名：P - 1 6 7 0，三菱化學食品（股份 有限））、蔗糖硬酯酸酯類（例如商品名：S - 1 6 7 0，三菱 化學食品（股份有限））、蔗糖月桂酸酯類（例如商品名 :L- 1 695 ’三菱化學食品（股份有限））等爲佳。聚氧乙 稀蓖麻油（polyethoxylatedcastoroil )特別以聚氧乙燦蓖 麻油（P〇ly〇xy35 Castor Oil，商品名：Cremophor EL或 EL-P，BASF日本（股份有限））等爲佳^聚氧乙烯氫化 蓖麻油（polyethoxylatedhydrogenatdcastoroil )特別以聚 氧乙嫌氫化蓖麻油 50 ( Polyoxyethylene Hydrogenated Castor Oil50)、聚氧乙稀氨化菌麻油 60 (Polyoxyethylene Hydrogenated Castor Oil60)等爲佳。聚氧乙烯聚丙烯甘 油共聚合體則以聚氧乙烯（160)聚氧丙烯（30)甘油醇 C商品名·· Pluronic F-68，旭電化工業（股份有限））爲 佳。聚甘油脂肪酸酯以月桂酸聚甘油（Decaglyn 1 - L， 曰光化學（股份有限））等爲佳。 疏水性界面活性劑可舉出蔗糖硬酯酸酯、蔗糖棕櫚酸 酯、蔗糖油酸酯、蔗糖月桂酸酯、蔗糖窬樹酸酯、蔗糖芥 酸酯等蔗糖脂肪酸酯類，山梨醇酐單硬酯酸酯、山梨醇酐 三硬酯酸酯、山梨醇酐單油酸酯、山梨醇酐三油酸酯、山 梨醇酐倍半油酸酯等山梨醇酐脂肪酸酯類，甘油醇單硬酯 -31 - 201113049 酸酯、甘油醇單油酸酯等甘油脂肪酸酯類，四異硬酯酸二 甘油酯、二異硬酯酸二甘油酯、單異硬酯酸二甘油酯等聚 甘油脂肪酸酯類等。 藥物一界面活性劑複合體係Solid-in-Water ( S/W )、 Solid-in-Oil ( S/O )及 Solid-in-Oil-in-Water ( S/O/W )， 而由該等所製造之製品群係醫藥品，或爲由食品（營養輔 助品）及化妝品（美妝品）所構成之醫療輔助製品。 5.藥物-界面活性劑複合體 本發明之藥物-界面活性劑複合體，係可將含有藥物 內包於界面活性劑中之1)直接以藥物-界面活性劑複合 體（Solid )之方式使用，2 )分散.溶解於親水性溶媒中 之Solid-in-Water ( S/W ) ，3 )分散•溶解於脂溶性溶媒 中之Solid-in-Oil ( S/0 )，及4 )將S/O分散.溶解於親水 性溶媒後之 Solid-in-Oil-in-Water ( S/0/W )等 4種藥物-界面活性劑複合體之製品進行製品化。 藥物-界面活性劑複合體可因應目的製成各式各樣的 型態’例如S爲粉體時，可直接以固體方式使用，當S爲液 狀或糊狀時可使用爲醫藥品、食品、化妝品等可使用之添 加物之型式使其吸附，並藉由進行粉體化而製作成固形化 物。 同樣的’使用含有S之凝膠、乳霜及軟膏製成液狀製 品時，可製作爲分散於親水性溶媒中之s/w、分散於脂溶 性或疏水性溶媒中之S/0、或將該S/ο分散於親水性溶媒後 -32- 201113049 之S/0/W等3種相異之形式。 本發明中之藥物-界面活性劑複合體，其最大特徵係 藉由將藥物內包於界面活性劑，可計畫安定性及提高吸收 性，且可掩蔽苦澀味或臭味等，改善對脂溶性之液劑脂分 散性。 以下針對本發明之藥物-界面活性劑複合體（S)， 與含藥物-界面活性劑複合體製品之各製品形式進行具體 說明。 5 -1 ·藥物一界面活性劑複合體（S ) 藥物-界面活性劑複合體（S )係可適當地將親水性 藥物、親水性界面活性劑、疏水性藥物、脂溶性界面活性 劑等進行乳化，藉由依需要以減壓乾燥及冷凍乾燥進行脫 水及脫溶媒而製造。 具體而言，S/O、S/0/W及 S/W在常溫狀態下的製造 ，可如圖1上半段所示方法進行。首先，在溶解槽a中將親 水性藥物或親水性界面活性劑以純水溶解。接著於溶解槽 b中將疏水性藥物或脂溶性界面活性劑溶解於脂溶性溶媒 中。S/Ο化時，分別將親水性藥物於溶解槽a，脂溶性界面 活性劑於溶解槽b，使用適當的分散媒進行完全溶解後， 再於乳化槽c進行乳化。另外，進行S/O/W或S/W時，與前 述相反，將親水性界面活性劑於溶解槽a，疏水性藥物（ 亦包含S/Ο化者）於溶解槽b，進行完全溶解後，再於乳化 槽c進行乳化。 -33- 201113049 另外，S/O、S/0/W及 s/w在加熱狀態下的製造，可 如圖1下半段所示方法進行。此時與常溫狀態下的製造相 同，於溶解槽a’，及溶解槽b’中，因應製造目的分別使藥 物液與界面活性劑溶解液進行溶解，但於常溫下溶解度較 低時，必須以加熱狀態（常溫〜1 2 1 °C )進行溶解。於此 狀態下爲抑制突沸（箭頭），而注入惰性氣體。氣體壓力 可根據與溶解溫度間的關係、槽的構造性自由加以設定， 但爲10大氣壓以下，通常以2大氣壓左右進行操作。在乳 化步驟的加熱，爲將藥物或界面活性劑之沸點相異的分散 媒進行乳化，以亦於溶解槽c’中注入惰性氣體等而抑制液 面（箭頭）爲佳。此時可於提高溶解性的同時進行乳化。 其後，將於溶解槽c’中製造之乳化物，以脫溶媒機d’，使 其噴霧氣化，於加熱且真空之狀態下進行脫溶媒。此時被 氣化而去除之分散媒，可於冷凝系統e之冷卻至-45 °C以下 之冷凝器進行收集，並於回收槽f被回收。如圖1上半段所 示之常溫乳化或下半段所示之加熱乳化，均可進行脫溶媒 (裝置d)及回收溶媒（裝置d) » 如上述所得之藥物-界面活性劑複合體（S )之造係 如圖2所示。當藥物爲難溶性且疏水性時，界面活性劑會 以疏水基朝向內側，親水基朝向外側之方式將藥物內包， 使難溶性藥物被親水性化。以下將其略稱爲親水型S或 Hydros。反之，藥物爲難溶性且親水性時，界面活性劑會 以親水基朝向內側，疏水基朝向外側之方式將藥物內包， 使難溶性藥物被脂溶性化。以下將其略稱爲疏水型S或 -34- 201113049Guidance for industry : Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system The solubility of BCS-based drugs in 25 ml buffer of pH 1. O~7.5 shows the maximum contained in 1 unit of preparation. When the drug content is above, it is classified as a water-soluble drug, and is classified as a poorly soluble drug in the following. In addition, poorly soluble drugs can be classified into hydrophilic poorly soluble drugs and hydrophobic poorly soluble drugs according to the balance between hydrophilicity and hydrophobicity. 4. Surfactant -28- 201113049 Sexuality in two-line, agent-type sub-living, yang, and various properties. Subagent i 4-U cation-inactive genus-like species, such as a surfactant-like active surface boundary, has a hydrophilic group and a hydrophobic group in the non-molecular, according to the balance between the hydrophilic group and the hydrophobic group ( HLB(R) can be classified as hydrophilic or hydrophobic (lipophilic). The balance between hydrophilicity and hydrophobicity of the surfactant is expressed by HLB(Hydrophilic Lipophilic Balance). HLB 采 0 to 20 indicates that the closer to 0, the higher the hydrophobicity, and the closer to 20, the higher the hydrophilicity. When the HLB of the hydrophilic surfactant is about 8 or more, it will form a 0/W type chyle, and the HLB of the hydrophobic surfactant will form a W/0 type chyle when it is less than 8. The surfactant used for S / 0 is a hydrophobic surfactant, and a hydrophilic surfactant of less than half of the amount of the hydrophobic surfactant may be added, preferably 10% or less. The S/0/W obtained by redispersing the S/deuterated oil agent in the aqueous phase can be prepared by adding a hydrophilic surfactant to the aqueous phase. In this case, one or a half of the hydrophilic surfactant may be added to the oil phase or the aqueous phase, or a hydrophilic surfactant, preferably 10% or less, or in the aqueous phase. The hydrophobic surfactant added to the aqueous phase of the hydrophobic surfactant is less than half of the hydrophilic surfactant, preferably 10% or less. The surfactant used for S/W is a hydrophilic surfactant. A hydrophobic surfactant of less than half the amount of the hydrophilic surfactant may be added, preferably 10% or less. Examples of the hydrophilic surfactant include anionic -29-201113049, a cationic, amphoteric, and nonionic surfactant as described below. As the anionic surfactant, a fatty acid soap, a naphthenic acid soap, a long-chain alcohol sulfate, a polyoxyethylene alkylphenyl ether sulfate, a fatty acid monoglyceride sulfate, a fatty acid monoalkylolamine sulfate can be used. , basic sulfonate, hydrazine:-sulfonated fatty acid salt, dialkyl sulfonated succinate, polyoxyethylene octyl phenyl ether sulfonate, alkyl benzene salt, polyoxyethylene alkyl benzene Alkyl ether phosphate salt, polyoxyethylene alkyl ether phosphate salt, sodium lauryl sulfate, and the like. As the cationic surfactant, a long-chain primary amine salt, an alkyltrimethylammonium salt, a dialkyldimethylammonium salt, an alkylpyrimidine salt, a polyoxyethylene alkylamine, an alkylimidazoline or the like can be used. As the amphoteric surfactant, ruthenium-alkyl, /3-aminopropionate, Ν-alkyl A-iminodipropionate or the like can be used. Hydrophilic nonionic surfactants can be used with higher alcohol ethylene oxide addenda, hospital based phenylethylene oxide addendum, fatty acid ethylene oxide addenda, polyol fatty acid ester ethylene oxygen addenda 'higher alkyl amine base Ethylene oxide addition, fatty acid amine-based ethylene oxide add-on's ethylene oxide addition of fats and oils, glycerin fatty acid ester, fatty acid ester of pentaerythritol, hospital ether of polyhydric alcohol, fatty acid amine of a home alcohol amine. As the nonionic surfactant, fatty acid esters such as sorbitol and sorbitan, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, sucrose fatty acid esters, polyoxygen can also be used. Polyethoxylated castoroil, polyethoxylated hydrogenated castor oil, polyoxyethylene polypropylene -30- 201113049 glycerin copolymer, glycerin fatty acid ester, polyglycerin fatty acid ester, and the like. The polyoxyethylene sorbitan fatty acid ester is particularly preferably a polysorbate fatty acid ester of 20, 40, 60 or 80. The polyethylene glycol fatty acid ester is particularly preferably monolauric acid polyethylene glycerol or the like. The sucrose fatty acid esters are particularly sucrose palmitates (for example, trade name: P - 1 6 7 0, Mitsubishi Chemical Foods Co., Ltd.), sucrose stearate esters (for example, trade name: S - 1 6 7 0, Mitsubishi Chemical Foods Co., Ltd., and sucrose laurate (for example, trade name: L-1 695 'Mitsubishi Chemical Foods Co., Ltd.) are preferred. Polyethoxylated castor oil (polyethoxylated castor oil), especially polyoxyethylene castor oil (P〇ly〇xy35 Castor Oil, trade name: Cremophor EL or EL-P, BASF Japan (share limited)), etc. The polyethoxylated hydrogenated castor oil (Polyoxyethylene Hydrogenated Castor Oil 50) and the polyoxyethylene Hydrogenated Castor Oil 60 are preferable. The polyoxyethylene polypropylene glycerol copolymer is preferably polyoxyethylene (160) polyoxypropylene (30) glycerol C, Pluronic F-68, and Asahi Chemical Industry Co., Ltd. (share limited). Polyglycerol fatty acid esters are preferably lauric acid polyglycerol (Decaglyn 1 - L, Shuguang Chemical (share limited)) and the like. Examples of the hydrophobic surfactant include sucrose fatty acid esters such as sucrose stearate, sucrose palmitate, sucrose oleate, sucrose laurate, sucrose eucalate, and sucrose erucate, and sorbitan is hard. Sorbitan fatty acid esters such as ester esters, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, glyceryl monostearate -31 - 201113049 Polyglycerol fatty acid esters such as glycerol fatty acid esters such as acid esters and glycerol monooleate, diisoglyceride diglycerides, diisostearic acid diglycerides, and monoisostearic acid diglycerides Classes, etc. a drug-surfactant composite system, Solid-in-Water (S/W), Solid-in-Oil (S/O), and Solid-in-Oil-in-Water (S/O/W), The manufactured product group is a pharmaceutical product or a medical auxiliary product composed of a food (nutrition aid) and a cosmetic (beauty product). 5. Drug-Spatial Agent Complex The drug-surfactant complex of the present invention can be used by directly containing a drug-surfactant complex (Solid) containing a drug in a surfactant. , 2) dispersion. Solid-in-Water (S/W) dissolved in a hydrophilic solvent, 3) dispersed-Solid-in-Oil (S/0) dissolved in a fat-soluble solvent, and 4) S /O dispersion. Products of four drug-surfactant complexes, such as Solid-in-Oil-in-Water (S/0/W), which are dissolved in a hydrophilic solvent, are processed. The drug-surfactant complex can be made into various types according to the purpose. For example, when S is a powder, it can be directly used as a solid, and when S is a liquid or a paste, it can be used as a medicine or a food. A form of an additive which can be used, such as a cosmetic, is adsorbed, and a solidified product is produced by powdering. Similarly, when a liquid product made of a gel, cream, or ointment containing S is used, it can be prepared as s/w dispersed in a hydrophilic solvent, S/0 dispersed in a fat-soluble or hydrophobic solvent, or The S/o is dispersed in three different forms such as S/0/W of -32-201113049 after the hydrophilic solvent. The drug-surfactant complex of the present invention is characterized in that the drug is encapsulated in a surfactant, the stability and the absorption are improved, and the bitterness or odor is masked, and the lipid is improved. Solubility agent grease dispersibility. Hereinafter, the drug-surfactant complex (S) of the present invention will be specifically described with respect to each product form of the drug-surfactant-containing composite product. 5 -1 · Drug-surfactant complex (S) The drug-surfactant complex (S) can suitably carry a hydrophilic drug, a hydrophilic surfactant, a hydrophobic drug, a fat-soluble surfactant, and the like. The emulsification is carried out by drying under reduced pressure and freeze-drying as needed to carry out dehydration and desolvation. Specifically, the manufacture of S/O, S/0/W, and S/W at a normal temperature state can be carried out as shown in the first half of Fig. 1. First, the hydrophilic drug or hydrophilic surfactant is dissolved in pure water in the dissolution tank a. Next, a hydrophobic drug or a fat-soluble surfactant is dissolved in the dissolution solvent b in a fat-soluble solvent. In the S/deuteration, the hydrophilic drug is dissolved in the dissolution tank a, and the fat-soluble surfactant is completely dissolved in the dissolution tank b using an appropriate dispersion medium, and then emulsified in the emulsification tank c. Further, when S/O/W or S/W is performed, in contrast to the above, the hydrophilic surfactant is dissolved in the tank a, and the hydrophobic drug (including the S/deuterizer) is dissolved in the tank b to be completely dissolved. And emulsified in the emulsification tank c. -33- 201113049 In addition, the manufacture of S/O, S/0/W and s/w in the heated state can be carried out as shown in the lower half of Figure 1. In this case, in the same manner as in the normal temperature state, the drug solution and the surfactant solution are dissolved in the dissolution tank a' and the dissolution tank b', respectively. However, when the solubility is low at normal temperature, it is necessary to Dissolved in a heated state (normal temperature ~ 1 2 1 °C). In this state, an inert gas is injected to suppress the boiling (arrow). The gas pressure can be set according to the relationship with the dissolution temperature and the structural property of the groove, but it is preferably 10 atmospheres or less, and is usually operated at about 2 atmospheres. In the heating in the emulsification step, it is preferred to emulsifie the dispersion medium having a different boiling point of the drug or the surfactant, and to inject an inert gas or the like into the dissolution tank c' to suppress the liquid surface (arrow). At this time, emulsification can be performed while improving solubility. Thereafter, the emulsion produced in the dissolution tank c' is degassed by the desolventizer d', and the solvent is removed by heating and under vacuum. The dispersion medium which is vaporized and removed at this time can be collected in a condenser cooled to -45 ° C or lower in the condensation system e, and recovered in the recovery tank f. The solvent-free (device d) and the recovered solvent (device d) can be carried out at room temperature emulsification or heat emulsification as shown in the upper half of Fig. 1 as shown in the first half of Fig. 1. The drug-surfactant complex obtained as described above ( The structure of S) is shown in Figure 2. When the drug is poorly soluble and hydrophobic, the surfactant encapsulates the drug in such a manner that the hydrophobic group faces inward and the hydrophilic group faces outward, so that the poorly soluble drug is rendered hydrophilic. Hereinafter, it will be referred to as a hydrophilic type S or Hydros. On the other hand, when the drug is poorly soluble and hydrophilic, the surfactant encapsulates the drug so that the hydrophilic group faces inward, and the hydrophobic group faces outward, so that the poorly soluble drug is fat-soluble. Hereinafter it will be referred to as a hydrophobic type S or -34- 201113049
LipoS。另外，藥物爲水溶性時，界面活性劑會以親水基 朝向內側，疏水基朝向外側之方式將藥物內包，使水溶性 藥物（亦稱作親水性藥物）被脂溶性化。以下將其略稱爲 疏水型S或LipoS。 5-1-1.更具體地可以下述方式來製造前述之Hydros或 Lipo S ° (I) 將藥物溶解及/或分散於水溶液至有機溶媒中 ，得溶解液及/或分散液之步驟， (II) 將疏水性界面活性劑或親水性以加熱等方法使 其液狀化並溶解，或溶解及/或分散於有機溶媒中，得溶 解液及/或分散液之步驟， (III )將步驟（I )所得之溶解液及/或分散液，與 步驟（II)所得之溶解液及/或分散液進行混合，乳化， 或分散之步驟，並且 (IV )將步驟（III )所得之乳化物或分散液，藉由進 行脫溶媒及/或脫水步驟，而可製造。 (上述步驟（I)及（II)何者先進行均可，亦可同時 進行。另外於上述之方法中，進而將藥物以維持微粉體狀 態而加入步驟（II)進行溶解或分散，或再進而將水加入 其中進行乳化亦可。） 5-1-2.首先針對製造LipoS時之各步驟更詳細地加以說明 -35- 201113049 步驟（I)將藥物溶解及/或分散於水溶液 使藥物溶解於水中時亦可使用溶解劑。藥物溶解劑可 爲檸檬酸、己二酸、乳酸、磷酸、碳酸化合物等水溶性的 酸或氫氧化鈉、氫氧化銨、磷酸鈉化合物等水溶性鹼基或 胺基酸及蛋白質、尿素、環糊精等包容化合物、或各種核 酸類、各種糖類等之一種或複數種。爲使其有效率地溶解 及或分散於水中，亦可加熱或進行加壓。 步驟（II)疏水性界面活性劑之溶解或分散 製造LipoS時所使用之界面活性劑，係可使用HLB自0 但未達8之疏水性界面活性劑，疏水性界面活性劑可舉出 蔗糖硬酯酸酯、蔗糖棕櫚酸酯、蔗糖油酸酯、蔗糖月桂酸 酯、蔗糖窬樹酸酯、蔗糖芥酸酯等蔗糖脂肪酸酯類，山梨 醇酐單硬酯酸酯、山梨醇酐三硬酯酸酯、山梨醇酐單油酸 酯、山梨醇酐三油酸酯、山梨醇酐倍半油酸酯等山梨醇酐 脂肪酸酯類，甘油醇單硬酯酸酯、甘油醇單油酸酯等甘油 脂肪酸酯類，四異硬酯酸二甘油酯、二異硬酯酸二甘油酯 、單異硬酯酸二甘油酯等聚甘油脂肪酸酯類等，可使該等 分散或溶解於有機溶媒中。該等疏水性界面活性劑可爲2 種以上，另外亦可添加疏水性界面活性劑一半量以下之親 水性界面活性劑，以1 〇%以下爲佳。 步驟（III)乳化或分散 將步驟（I)所得之溶解及/或分散之藥物水溶液（ -36- 201113049 以下亦稱作步驟（I)水溶液）’以及步驟（Π)所得之溶 解及/或分散於疏水性界面活性劑後之有機溶媒（以下亦 稱作步驟（II )之有機溶媒）進行混合，並進行乳化。可 將步驟（I)水溶液加入步驟（Π)之有機溶媒中，相反地 亦可將步驟（II)之有機溶媒加入步驟（I)水溶液，較適 當的方式爲將步驟（I)水溶液與步驟（Π)有機溶媒保持 加熱加壓的狀態而導入乳化槽。 步驟（IV)脫溶媒及/或脫水 該等脫溶媒及/或脫水之步驟可以周知之方法而進行. ，例如可以真空冷凍乾燥及減壓乾燥，氮氣吹靜等進行， 但並非限定於該等方法，可因應目的選擇最適當的乾燥方 法。 另外所得S之「界面活性劑一藥物複合體」，不僅爲使 用界面活性劑之性質而使水分散於脂中，於使其吸附於二 氧化矽等適當的載體之主藥，亦可使用於製造散劑、顆粒 劑、錠劑、膠囊劑等固形製劑。 5-卜3.其次，更詳細地說明製造Hydros時之各步驟。 步驟（I)將疏水性藥物溶解及/或分散於有機溶媒中 於有機溶媒中之溶解或分散 使藥物溶解於有機溶媒時，爲有效率地使藥物溶解及 /或分散於有機溶媒，可加熱或進行加壓》 -37- 201113049 步驟（11 )親水性界面活性劑之溶解或分散 製造Hydros時所使用之界面活性劑，係可使 8以上者，可舉出以下記載之陰離子性、陽離子 、非離子性界面活性劑。 陰離子性界面活性劑可使用脂肪酸性皂、環 皂、長鏈醇硫酸酯、聚氧乙烯烷基苯基醚硫酸酯 酸單甘油酯硫酸酯、脂肪酸單烷基醇胺硫酸酯、 鹽、α-磺酸化脂肪酸鹽、二烷基磺酸化丁二酸 乙烯辛基苯基醚磺酸鹽、烷基苯磺酸鹽、聚氧乙 基醚磷酸酯鹽、聚氧乙烯烷基醚磷酸酯鹽、月桂 等。 陽離子性界面活性劑可使用長鏈一級胺鹽、 基銨鹽、二烷基二甲基銨鹽、烷基嘧啶鹽、聚氧 胺、烷基咪唑琳等。 兩性界面活性劑可使用Ν -烷基、/3 -胺基丙 烷基/3-亞氨基二丙酸鹽等。 水溶性的非離子性界面活性劑可使用高級醇 加物、烷基苯基乙烯氧附加物、脂肪酸乙烯氧附 元醇脂肪酸酯乙烯氧附加物、高級烷基胺基乙烯 '脂肪酸胺基乙烯氧附加物、油脂之乙烯氧附加 脂肪酸酯、季戊四醇之脂肪酸酯、多元醇之烷基 醇胺類之脂肪酸胺等。非離子性界面活性劑中， 例如山梨醇及山梨醇酐之脂肪酸酯、聚氧乙烯山 肪酸酯、聚乙烯乙二醇脂肪酸酯、蔗糖脂肪酸酯 用HLB爲 性、兩性 烷甲酸性 鹽、脂肪 鹼性磺酸 鹽、聚氧 烯烷基苯 基硫酸鈉 烷基三甲 乙烯烷基 酸鹽、Ν- 乙烯氧附 加物、多 氧附加物 物、甘油 醚、烷基 亦可使用 梨醇酐脂 、聚氧乙 -38- 201113049 稀蓖麻油（polyethoxylatedcastoroil)、聚氧乙稀氫化蓖 麻油(polyethoxylatedhydrogenatedcastoroil )、聚氧乙稀 聚丙烯甘油共聚合體、甘油脂肪酸酯、聚甘油脂肪酸酯等 。聚氧乙烯山梨醇酐脂肪酸酯特別以聚山梨醇酐脂肪酸酯 20、40、60、80等爲佳。聚乙烯乙二醇脂肪酸酯特別以單 月桂酸聚乙烯甘油醇等爲佳。蔗糖脂肪酸酯特別以蔗糖棕 櫚酸酯類（例如商品名：P - 1 6 7 0，三菱化學食品（股份有 限））、蔗糖硬酯酸酯類（例如商品名：S - 1 67 0，三菱化 學食品（股份有限））、蔗糖月桂酸酯類（例如商品名： L-169S，三菱化學食品（股份有限））等爲佳。聚氧乙烯 蓖麻油（polyethoxylatedcastoroil )特別以聚氧乙烯蓖麻 油(Polyoxy3 5 Castor oil，商品名：Cremophor EL 或 EL-P ’ BASF日本（股份有限））等爲佳。聚氧乙烯氫化蓖麻 油（polyethoxylatedhydrogenatedcastoroil )特別以聚氧乙 稀氫化蓖麻油 50 ( Polyoxyethylene Hydrogenated Castor 〇il50 ) '聚氧乙嫌氮化蔑麻油60 ( Polyoxyethylene Hydrogenated Castor Oil60)等爲佳。聚氧乙烯聚丙烯甘 油共聚合體則以聚氧乙烯（160)聚氧丙烯（30)甘油醇 (商品名：Pluronic F-68，旭電化工業（股份有限））爲 佳。聚甘油脂肪酸酯以月桂酸聚甘油（Decaglyn 1 — L， 曰光化學（股份有限））等爲佳。 可含有該等親水性界面活性劑之1種或2種以上。另外 ’以2種以上爲佳，可添加親水性界面活性劑一半量以下 之疏水性界面活性劑，以1 0 %以下爲佳。 -39- 201113049 步驟（ΠΙ)乳化或分散 將步驟（I)所得之溶解及/或分散之藥物有機溶媒 (以下亦稱作步驟（Ο有機溶媒），以及步驟（Π )所得 之溶解及/或分散於親水性界面活性劑後之水溶液（以下 亦稱作步驟（II)之水溶液）進行混合，並進行乳化。可 將步驟（I)有機溶媒加入步驟（II)水溶液之中，相反地 亦可將步驟（II)之水溶液加入步驟（I)有機溶媒，較適 當的方式爲將步驟（I)有機溶媒與步驟（II)水溶液保持 加熱加壓的狀態而導入乳化槽。於製造前述任一LipoS或 Hydros時，乳化以使用薄膜旋轉型高速攪拌機、高攪拌機 、葉輪攪拌機、IPROS真空乳化機爲佳，需要注意的是以 氣體壓力抑制突沸的同時，進行高速攪拌時之控制閥軸封 的氣密性十分重要，可使用機械軸封等。 步驟（IV)脫溶媒及/或脫水 該等脫溶媒及/或脫水之步驟可以周知之方法而進行 ，例如可以真空冷凍乾燥及減壓乾燥，氮氣吹淨等進行， 但並非限定於該等方法，可因應目的選擇最適當的乾燥方 法。 另外所得S之「界面活性劑-藥物」，不僅爲使用界面 活性劑之性質而使水分散於脂中，於使其吸附於二氧化矽 等適當的載體之主藥，亦可使用於製造散劑、顆粒劑、錠 劑、膠囊劑等固形製劑。 -40- 201113049 5-2. Solid-in-Water ( S/W ) 將藥物特別係疏水性難溶性藥物子，分散或名 解槽a或溶解槽b之後，將界面活性劑，溶解於溶 溶解槽b，特別係將富親水性之界面活性劑溶解於 之後，於乳化槽c進行乳化，由於以脫水或脫溶g 將藥物-界面活性劑複合體（Hydros )分散、溶角 親水性分散媒（親水性溶媒），可製造S/W。其構 所示。 5-3 . Solid-in-Oil ( S/Ο ) 將藥物特別係水溶性藥物溶解於溶解槽a時， 富疏水性之界面活性劑溶解於溶解槽a，或特別保 槽b進行溶解後，於乳化槽（；進行乳化，進行脫水驾 後，製造藥物-界面活性劑複合體（LipoS )之g 分散於可使用植物油等之醫藥品、食品、化妝品；^ 分散媒（脂溶性溶媒，Oil )，而可製造S/Ο。其損 4所示。 更具體而言，S/O係藉由包含下述步驟之製缝 進行製造。 (A)將藥物溶解及/或分散於水及醇等揮i 性溶媒中，得溶解液及/或分散液之步驟， (B )將疏水性界面活性劑以加熱等方法使3 並溶解，或溶解及/或分散於有機溶媒中，得溶角 f解於溶 解槽a或 溶解槽a :，藉由 ;於水等 造如圖3 同時將 以溶解 脫溶媒 ，藉由 脂溶性 造如圖 方法可 性親水 液狀化 液及/ -41 - 201113049 或分散液之步驟， (C)將步驟（A)所得之溶解液及/或分散液，與步 驟（B )所得之溶解液及/或分散液進行混合，乳化，或 分散之步驟 (D )將步驟（C )所得之乳化物或分散液，進行脫溶 媒及/或脫水步驟，以及 (E)將步驟（D)所得之藥物一界面活性劑複合體製 品’分散於植物油及合成油脂之一種以上的脂溶性溶媒中 。且前述之步驟（A)及步驟（B)何者先進行均可，亦可 同時進行。 另外，於上述之步驟（A)中將藥物溶解及分散於水 溶液中之方法’爲提高溶解性使用各式各樣的方法。例如 可舉出使用pH調整劑調製至溶解度高之範圍的方法，及添 加溶解輔助劑，進而加熱或加熱且以惰性氣體進行加壓等 方法。 且於前述方法中，可進而將藥物以維持微粉體狀態而 加入步驟（B )進行溶解或分散，或再進而將水加入其中 進行乳化亦可。另外前述步驟（B )將疏水性界面活性劑 以加熱等方法使其液狀化之方法，可舉出加熱或加熱且以 惰性氣體進行加壓等方法。 5-4. Solid-in-Oil-in-Water ( S/0/W) 將於上述5-3所製造之S/Ο，藉由分散或溶解於水等親 水性溶媒中，而可製造S/0/W，其構造如圖5所示。 -42- 201113049 另外S/0/W可根據包含 (F )將賞述步驟（E )中所得之S/Ο，分散於純水及 緩衝溶液等親水性溶媒中之步驟之製造方法而進行製造。 5-5. S/W係由下述步驟所構成之製造方法而進行製造。 (甲）將藥物特別係疏水性難溶性藥物，溶解及/或 分散於有機溶媒中，得溶解液及/或分散液之步驟， (乙）將親水性界面活性劑以加熱等方法進行液狀化 及溶解，或將其溶解及/或分散於水及醇等揮發性親水性 溶媒中，得溶解液及/或分散液之步驟， (丙）將步驟（甲）所得之有機溶媒之溶解液及/或 分散液，加入步驟（乙）所得之溶解液及/或分散液中， 進行乳化或分散之步驟， (丁）將步驟（丙）所得之乳化物或分散液，藉由進 行脫溶媒及/或脫水而得S之步驟， (戊）可藉由步驟（丁）所得之S分散於純水及緩衝 液等親水性溶媒中之步驟所成之製造方法製造。且前述之 步驟（甲）及步驟（乙）何者先進行均可，亦可同時進行 〇 前述步驟（乙）中，可進而將藥物以維持微粉體狀態 進行溶解或分散，或再進而加入有機溶媒進行乳化亦可。 另外前述步驟（乙）中將親水性界面活性劑以加熱等方法 使其液狀化之方法，可舉出加熱或加熱且以惰性氣體進行 加壓等方法。 -43- 201113049 另外於上述之5-2至5-5中，可對步驟（A) 、 （b)、 (C)及步驟（甲）、（乙）、（丙）任一個以上的步驟 ，以注入不可燃氣體之狀態下進行爲佳。注入之氣體爲惰 性氣體，且爲1大氣壓以上，10大氣壓以下則更佳。於步 驟（B ) 、（ C)及步驟（甲）、（丙）進行溶解、分散或 乳化時，於槽之液體上方的氣相部分，注入氣體或不可燃 氣體爲最佳。注入之氣體爲惰性氣體，且爲1大氣壓以上 ，10大氣壓以下則更佳。 上述之不可燃氣體可選擇氮氣、碳酸、氨氣、氬氣之 任一種或2種以上。 步驟（D)或步驟（丁）之脫溶媒及/或脫水，可以 真空冷凍乾燥、減壓乾燥、微波膨化乾燥、冷凍粉碎乾燥 、氮氣吹淨等方法進行。可藉由該步驟而得藥物爲固體狀 態被內包之藥物一界面活性劑複合體製品（S )。於本專 利中’藥物藉由該等方法，經脫溶媒或/及脫水後狀態者 定義爲「藥物爲以固體狀態被內包」。 於此所使用之界面活性劑，若爲可使用於醫藥品、食 品、化妝品者，則均可使用，例如製造更微小的藥物一界 面活性劑複合體（S)時，可因應目的將藥物分散於親水 性溶媒或脂溶性溶媒後，再選擇Hydros或LipoS，進而選 擇親水性界面活性劑或疏水性界面活性劑之種類。 使用之界面活性劑之種類界面活性劑種類，依是否可 溶解、分散於親水性溶媒或脂溶性溶媒中，及製品目的而 有各式各樣的種類，本發明並非因此而有任何限制。另外 -44- 201113049 亦可混合界面活性劑而使用。 使用於本發明之藥物一界面活性劑複合體之界面活性 劑，若爲可使用於醫藥品、食用、或化妝品用者則無特別 限制，可舉出離子性或非離子性界面活性劑，離子性界面 活性劑則有陽離子性、陰離子性、兩性界面活性劑。可選 擇該等之1種以上。 s/ο用之界面活性劑係疏水性界面活性劑，亦可添加 疏水性界面活性劑一半量以下之親水性界面活性劑’以 10%以下爲佳。 用於將S/ο化後之油劑再分散於水相所得之s/0/w者’ 可於水相中添加親水性界面活性劑而進行調製。此時’無 論於油相或水相中，可添加親水性界面活性劑量之—半的 疏水性界面活性劑，或親水性界面活性劑’以10%以下爲 佳。另外亦可於水相中添加疏水性界面活性劑。水相中添 加之疏水性界面活性劑爲親水性界面活性劑半量以下’以 10%以下爲佳。 S/W用之界面活性劑係親水性界面活性劑。可添加親 水性界面活性劑半量以下之疏水性界面活性劑’以10 %以 下爲佳。 親水性的界面活性劑可舉出如下所述之陰離子性、陽 離子性、兩性、非離子性界面活性劑。陰離子性界面活性 劑可使用脂肪酸性皂、環烷甲酸性皂、長鏈醇硫酸醋、聚 氧乙烯烷基苯基醚硫酸酯鹽、脂肪酸單甘油酯硫酸醋 '脂 肪酸單烷基醇胺硫酸酯、鹼性磺酸鹽、α -磺酸化脂肪酸 -45- 201113049 鹽、二烷基磺酸化丁二酸鹽、聚氧乙烯辛基苯基醚磺酸鹽 、烷基苯磺酸鹽、聚氧乙烯烷基苯基醚磷酸酯鹽、聚氧乙 烯烷基醚磷酸酯鹽、月桂基硫酸鈉等。陽離子性界面活性 劑可使用長鏈一級胺鹽、烷基三甲基銨鹽、二烷基二甲基 銨鹽、烷基嘧啶鹽、聚氧乙烯烷基胺、烷基咪唑啉等。兩 性界面活性劑可使用N-烷基、冷-胺基丙酸鹽、N-烷基召-亞氨基二丙酸鹽等。親水性的非離子性界面活性劑可使用 高級醇乙烯氧附加物、烷基苯基乙烯氧附加物、脂肪酸乙 烯氧附加物、多元醇脂肪酸酯乙烯氧附加物、高級烷基胺 基乙烯氧附加物、脂肪酸胺基乙烯氧附加物、油脂之乙烯 氧附加物、甘油脂肪酸酯、季戊四醇之脂肪酸酯、多元醇 之烷基醚、烷基醇胺類之脂肪酸胺等。 非離子性界面活性劑中，亦可使用例如山梨醇及山梨 醇酐之脂肪酸酯、聚氧乙烯山梨醇酐脂肪酸酯、聚乙烯乙 二醇脂肪酸酯、蔗糖脂肪酸酯、聚氧乙烯蓖麻油（ polyethoxylatedcastoroil )、聚氧乙烯氫化蓖麻油（ polyethoxylatedhydrogenatedcastoroil)、聚氧乙烯聚丙烯 甘油共聚合體、甘油脂肪酸酯、聚甘油脂肪酸酯等。聚氧 乙烯山梨醇酐脂肪酸酯特別以聚山梨醇酐脂肪酸酯20、40 、60、8 0等爲佳。聚乙烯乙二醇脂肪酸酯特別以單月桂酸 聚乙烯甘油醇等爲佳。蔗糖脂肪酸酯特別以蔗糖棕櫚酸酯 類（例如商品名：P-1 670，三菱化學食品（股份有限）） 、蔗糖硬酯酸酯類（例如商品名：S - 1 6 7 0，三菱化學食品 (股份有限））、蔗糖月桂酸酯類（例如商品名：L-1 695 -46- 201113049 ，三菱化學食品（股份有限））等爲佳。聚氧乙嫌蓖麻油 (polyethoxylatedcastoroil )特別以聚氧乙烯蓖麻油（ Polyoxy35 Castor Oil，商品名：Cremophor EL 或 EL-P， BASF日本（股份有限））等爲佳。聚氧乙烯氫化蓖麻油 (polyethoxylatedhydrogenatedcastoroil )特別以聚氧乙稀 氮化菌麻油 50 ( Polyoxyethylene Hydrogenated Castor 0il5 0 )、聚氧乙烧氫化蓖麻油60 ( Polyoxyethylene Hydrogenated Castor Oil60)等爲佳。聚氧乙烯聚丙烦甘 油共聚合體則以聚氧乙烯（160 )聚氧丙烯（30 )甘油醇 (商品名：Pluronic F-68，旭電化工業（股份有限））爲 佳。聚甘油脂肪酸酯以月桂酸聚甘油（Decaglyn 1 - L， 曰光化學（股份有限））等爲佳。 疏水性界面活性劑可舉出蔗糖硬酯酸酯、蔗糖棕櫚酸 酯、蔗糖油酸酯、蔗糖月桂酸酯、蔗糖窬樹酸酯、蔗糖芥 酸酯等蔗糖脂肪酸酯類，山梨醇酐單硬酯酸酯、山梨醇酐 三硬酯酸酯、山梨醇酐單油酸酯、山梨醇酐三油酸酯、山 梨醇酐倍半油酸酯等山梨醇酐脂肪酸酯類，甘油醇單硬酯 酸酯、甘油醇單油酸酯等甘油脂肪酸酯類，四異硬酯酸二 甘油酯、二異硬酯酸二甘油酯、單異硬酯酸二甘油酯等聚 甘油脂肪酸酯類等。 該等界面活性劑可使用2種以上。 使用於本發明之S/O或S/0/W之脂溶性溶媒，若爲可使 用於醫藥品、食用、或化妝品用之油成分有機溶媒則無特 別限制，例如可舉出植物油、動物油、中性脂質（單取代 -47- 201113049 、雙取代、或三取代之甘油酯）、合成油脂、以及/或固 醇衍生物。 具體而言植物油可舉出大豆油、棉實油、菜籽油、芝 麻油、玉米油、花生油、紅花油、葵花油、橄欖油、荷荷 芭油、紫蘇油等，動物油可舉出牛脂、豬油、魚油等，中 性脂肪可舉出三油精、三次亞麻油精、三棕櫚油精、三硬 酯油精、三肉宣蔻油精或三花生四烯酸油精等，合成油脂 則可舉出肉宣蔻酸異丙酯、氮酮、己烷、甲苯、氯仿、二 氯甲烷、醋酸乙酯、二甲基乙醯乙醯胺、環己烷、丙酮、 二甲基亞颯、庚烷、戊烷等，固醇衍生物可舉出油酸膽固 醇酯、次亞麻酸膽固醇酯、肉宣蔻酸膽固醇酯、棕櫚酸膽 固醇酯、或三花生四烯酸膽固醇酯等。該等油脂亦可使用 2種以上。 較佳之油成分可舉出甘油酯及以其爲主成分之植物油 及動物油。實用者係大豆油、芝麻油、橄欖油、角鯊烯及 角鯊烷爲佳，特別以經高度純化之芝麻油及橄欖油爲佳。 本發明之藥物-界面活性劑複合體（S)中之藥物與 界面活性劑量依親水性或疏水性等種類而異，但相對於藥 物之界面活性劑，重量比（界面活性劑/藥物）以1〜50 之範圍爲佳，2〜30之範圍內更佳，5〜20之範圍最佳。 6.配合劑/製劑化 根據本發明申請案，藉由藥物之水溶性、親水性難溶 性、或疏水性難溶性之性質，將依據上述5.所調製的藥物 -48- 201113049 一界面活性劑複合體（s )製成S/O、S/W或s/o/w，可藉 由變更對藥物溶媒及凝膠之表面特性，作爲配合劑而可以 一劑型之方式進行製劑化》例如水溶性藥物可直接分散於 親水性溶劑中，但爲使水溶性藥物以外者以及水溶性藥物 分散於親水性溶媒，可進行S/W化或s/o/w化。而疏水性 難溶性藥物亦可直接分散於脂溶性溶劑中，但可將其以外 者進行s/ο化後，再使其分散於脂溶性溶劑。 另外藉由將藥物製成藥物-界面活性劑複合體（S ) ，可使一般於單一溶媒中無法使其共存之複數種藥物，例 如容易互相引起化學反應之藥物，藉由於各自的溶媒中形 成藥物-界面活性劑複合體相互分離而存在，可例如不引 起反應，而以安定的狀態進行保存。 於本發明中，被分散於溶媒中之藥物並未限定爲2種 ，本發明申請案包含使2種以上任意種類之藥物分散於同 一溶媒中。另外作爲配合劑使用之藥物，係可使用揭示於 2.藥物之藥物。 6-1.水溶性藥物與難溶性藥物之1劑化 可將水溶性藥物與難溶性藥物，依據上述5.調製爲 藥物-界面活性劑複合體（S )後，再藉由製成S/0、S/W 或S/O/W，作爲配合劑而可以一劑型之方式進行製劑化。 此處水溶性藥物可舉出維他命C、半胱胺酸、羥基脯 胺酸、天冬胺酸Na、麩醯胺酸及精胺酸。親水性難溶性藥 物可舉出例如稱作支鏈胺基酸之BCAA (白胺酸、異白胺 -49- 201113049 酸、纈胺酸）。疏水性難溶性藥物可舉出例如CoQlO。 藥物的種類並未限定於分別使用1種，亦可使用複數 種種類。 6-1 -1 .具體而言將水溶性藥物與疏水性難溶性藥物分散於 親水性溶媒（例如水溶液）進行製劑化時，可以下述方式 進行。 (1 )維持水溶性藥物的水溶性，將疏水性難溶性藥 物製爲Hydros並再製爲S/W，可分散於親水性溶媒中。 (2 )將水溶性藥物製爲S/0/W，亦可將疏水性難溶性 藥物製爲Hydros並再製爲S/ W。 親水性溶媒爲水性溶媒、純水及緩衝液等，具體可舉 出以下者。例如注射用水、生理食鹽水、磷酸緩衝液、林 格氏液、醋酸緩衝液、檸檬酸緩衝液、硼酸緩衝液、酒石 酸緩衝液、Tris緩衝液、Macrogol 400、甘油、丙二醇、 丙醇、乙醇及該等之混合液。 6-1 -2 .將水溶性藥物與疏水性難溶性藥物分散於脂溶性溶 媒進行製劑化時，可直接將疏水性難溶性藥物分散於脂溶 性溶劑中，將水溶性藥物根據上述方法，製爲LipoS或製 爲S/0，而可進行分散於脂溶性溶媒之製劑化。 脂溶性溶媒若爲可使用於醫藥品、食用、或化妝品用 之油成分有機溶媒則無特別限制，例如可舉出植物油、動 物油、中性脂質（單取代、雙取代、或三取代之甘油酯） -50- 201113049 、合成油脂、以及/或固醇衍生物。 具體而言植物油可舉出大豆油、棉實油、菜籽油、芝 麻油、玉米油、花生油、紅花油、葵花油、橄欖油、荷荷 芭油、酪梨油、紫蘇油等，動物油可舉出牛脂、豬油、魚 油等，中性脂肪可舉出三油精、三次亞麻油精、三棕櫚油 精、三硬酯油精、三肉竟蔻油精或三花生四烯酸油精等， 合成油脂則可舉出肉a蔻酸異丙酯、氮酮、己烷、甲苯、 氯仿、二氯甲烷、醋酸乙酯、二甲基乙醯乙醯胺、環己烷 、丙酮、二甲基亞颯、庚烷、戊烷等，固醇衍生物可舉出 油酸膽固醇酯、次亞麻酸膽固醇酯、肉豈蔻酸膽固醇酯、 棕櫚酸膽固醇酯、三花生四烯酸膽固醇酯等。該等油脂亦 可使用2種以上。 較佳之油成分可舉出甘油酯及以其爲主成分之植物油 及動物油。實用者係大豆油、芝麻油、橄欖油、角鯊烯及 角鯊烷爲佳，特別以經高度純化之芝麻油及橄欖油爲佳。 進而可將上述之藥物分散脂溶性溶媒，塡充於軟膠囊 及硬膠囊中而進行製劑，進而亦可將該等軟膠囊及硬膠囊 以氣泡包裝進行包裝。 6-1 -3 .將水溶性藥物與親水性難溶性藥物分散於脂溶性溶 媒時，均可使其爲LipoS，藉由分散於油相中製成S/Ο，而 可分散於脂溶性溶媒中。脂溶性溶媒可使用如上述6-1 -2中 所記載之脂溶性溶劑。 -51 - 201113049 6-1 -4.將水溶性藥物與親水性難溶性藥物分散於親水性溶 媒時’可使親水性難溶性藥物爲LipoS後，再分散於油相 中製成S/Ο，接著分散於水相中製成s/0/W，而可分散於親 水性溶媒中。親水性溶媒可使用如上述6-1 -1中所記載之親 水性溶媒。 6-1 -5 .將水溶性藥物與難溶性藥物以固體或凝膠狀態而使 用時，可將其他的固體成分或凝膠成分，與Hydros及/或 L i ρ 〇 S進行混合。 其他固體成分或凝膠成分可舉出羧甲基纖維素Na、海 藻酸Na、卡拉膠、果膠、洋菜、結蘭膠、葡甘露聚糖 '聚 乙烯吡咯烷酮、羧乙烯聚合物、黃耆膠、丙烯醯胺、聚乙 二烯醇等。 可藉由凝膠化基材的效果，將親水性難溶性藥物亦製 爲LipoS後，而可分散於水性凝膠中。 6-2.爲例如溶媒中會產生化學反應，無法使其共存之複 數種藥物之1劑型化 本發明中所指之化學反應係包含任一種會對藥物產生 影響的化學反應，例如可舉出氧化還原反應、螯合反應、 陰離子一陽離子反應、加成反應 '胺羰反應，但並未限定 於該等反應。 6-2-1.引起氧化還原反應之化合物 -52- 201113049 以配合劑之組合，無法使具有氧化作用之藥物與具有 還原作用之藥物以一劑型之方式進行配合，但根據本專利 技術則變成可能。 具有氧化作用之藥物有例如邁可那挫（Miconazole Nitrate)、愛速得（Isosorbide Dinitrate)、拿必樂點眼 液（Naphazoline Nitrate )等。具有還原作用之藥物有例 如維他命C、半胱胺酸' 乙醯半胱胺酸、肉桂醛、維他命E 、8胡蘿蔔素、葉酸、尿酸、泛醌、二十六烷五烯酸乙酯 、麩氨基硫、亞硫酸鈉等。 6-2-2.陰離子系藥物與陽離子系藥物 以配合劑之組合，無法使酸性藥物（陰離子系藥物） 與鹼性藥物（陽離子系藥物）以一劑型之方式進行配合， 但根據本專利技術則變成可能。 陰離子系藥物可舉出腺核苷三磷酸、RN A及DN A等核 酸系藥物、丙戊酸、二丙磺胺苯甲酸、盤尼西林類、引朵 美洒辛（indomethacin)、聯苯乙酸、華法林（warfarin) 、水楊酸、阿斯匹靈、苯巴比妥、甘菊藍磺酸鈉、保脈暢 ，（Alprostadil)、氨來咕諾（Amlexanox)、甘草酸等。 陽離子系藥物可舉出亞德利亞黴素（doxorubicin )、奧洛 他定（Olopatadine)、多巴胺、貝尼第平（benidipine) 、小諾黴素（Micironomicin)等胺基配糖體系抗生素、胃 利空懸液劑（Domperidone)、溫諾平（Vinorelbine)、 耐嗯伴（Tropisetron) '施免（Cimetidine)、普利心律 -53- 201113049 (Procainamide)、四環黴素、妥富腦（Imipramine)、 安非他命、佩西汀（Meperidine )等。 6-2-3.螯合化藥物 以配合劑之組合，無法使可行成錯合物（螯合物）即 會引起金屬離子交換反應之藥物以一劑型之方式進行配合 ，但根據本專利技術則變成可能。 例如氫氧化鋁與新萘醌類藥物、金屬螯合藥物（Ca-2Na-EDTA、二疏丙醇、德斯芬（Deferoxamine)，與含金 屬離子之藥物（氣銘胺明（Cyanocobalamin)、甲基銘胺 明（Methylcobalamin) 、Cisplatin系白金錯合物抗癌劑、 Aceglutamide Aluminum)。進而將 Cisplatin系白金錯合物 抗癌劑（Cisplatin、Carboplatin、Nedaplatin、Oxaliplatin 等），與生理食鹽水及林格氏液等含Na離子及Ca離子之液 體配合時、會引起配位子交換，但藉由本專利技術之界面 活性劑複合體化，使可進行配合。 6-2-4.胺羰反應 以配合劑之組合，由於胺基酸與含胺基之藥物，會與 糖類及含醛基之藥物引起所謂胺羰反應而無法進行配合， 但根據本專利技術則變成可能》 胺基酸及含胺基之藥物可舉出各種胺基酸、干擾素、 人類生長荷爾蒙、顆粒球增殖因子、胰島素、Calcitonin Salmon、其他蛋白質生肽類藥物、多巴胺、醋磺胺甲噁唑 -54- 201113049 、尿囊素、去甲麻黃、氨基菲林等。另外糖類及含醛基之 藥物可舉出葡萄糖 '乳糖、蔗糖、醋葡醛內酯（ Aceglatone)、三节糖苷（Tribenoside)、阿糖腺苷（ Vidarabine)等。 6-2-5.製劑化 上述會產生化學反應之複數種藥物，每一種藥物可被 分類爲水溶性藥物、親水性難溶性藥物、疏水性難溶性藥 物。 上述之複數種藥物均爲水溶性藥物時，（甲）將每一 種藥物製成藥物-界面活性劑複合體（LipoS )，並分散 於油相（Oil )中，成爲以Solid-iii-Oil ( S/0 )之型態分散 於脂溶性藥物之製劑，或爲（乙）使每種藥物製成之藥物 —界面活性劑複合體（LipoS)並分散於油相（Oil)後之 Solid-in-Oil ( S/Ο )，再進而分散於水相中，&Solid-in-Oi 1-in-Water ( S/0/W )之型態，成爲分散於親水性溶媒之 製劑。 上述之複數種藥物均爲疏水性難溶性藥物時，使每種 藥物以藥物-界面活性劑複合體（Hydros )並分散於水相 (Water )後之Solid-in-Water ( S/W )型態，成爲分散於 親水性溶媒之製劑。 上述之複數種藥物均爲親水性難溶性藥物時，將每種 藥物之藥物-界面活性劑複合體（LipoS )分散於油相（ ΟΠ )後之Solid-in-Oil ( S/Ο )，再進而以分散於水相後之 -55- 201113049LipoS. Further, when the drug is water-soluble, the surfactant encapsulates the drug with the hydrophilic group facing the inside and the hydrophobic group facing the outside, so that the water-soluble drug (also referred to as a hydrophilic drug) is fat-soluble. Hereinafter, it will be referred to as a hydrophobic type S or LipoS. 5-1-1. More specifically, the aforementioned Hydros or Lipo S ° (I) may be prepared by dissolving and/or dispersing the drug in an aqueous solution to an organic solvent to obtain a solution and/or a dispersion. (II) a step of dissolving and dissolving a hydrophobic surfactant or hydrophilicity by heating or the like, or dissolving and/or dispersing in an organic solvent to obtain a solution and/or a dispersion, (III) The solution and the dispersion obtained in the step (I) are mixed with the solution and/or the dispersion obtained in the step (II), emulsified, or dispersed, and (IV) the emulsion obtained in the step (III) The material or dispersion can be produced by carrying out a solvent removal and/or dehydration step. (The above steps (I) and (II) may be carried out first or simultaneously. In addition, in the above method, the drug is further added to the step (II) to be dissolved or dispersed in a state of maintaining the fine powder, or further Water may be added thereto for emulsification.) 5-1-2. First, the steps for producing LipoS are explained in more detail - 35 - 201113049 Step (I) Dissolving and/or dispersing the drug in an aqueous solution to dissolve the drug A solvent can also be used in water. The drug dissolving agent may be a water-soluble acid such as citric acid, adipic acid, lactic acid, phosphoric acid or a carbonic acid compound, or a water-soluble base or amino acid such as sodium hydroxide, ammonium hydroxide or sodium phosphate compound, and a protein, urea, or a ring. One or a plurality of inclusive compounds such as dextrin or various nucleic acids and various sugars. In order to be efficiently dissolved and or dispersed in water, it may be heated or pressurized. Step (II) Dissolution or Dispersion of Hydrophobic Surfactant The surfactant used in the manufacture of LipoS may be a hydrophobic surfactant having an HLB of from 0 but less than 8, and a hydrophobic surfactant may be exemplified by sucrose hard. Sucrose fatty acid esters such as ester ester, sucrose palmitate, sucrose oleate, sucrose laurate, sucrose eucalyptus, sucrose erucic acid ester, sorbitan monostearate, sorbitan tristearate Sorbitan fatty acid esters such as acid esters, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, glycerol monostearate, glycerol monooleate, etc. A glycerol fatty acid ester, a polyglycerol fatty acid ester such as diisostearic acid diglyceride, diisostearic acid diglyceride or monoisostearic acid diglyceride, which can be dispersed or dissolved in an organic solvent. . These hydrophobic surfactants may be used in combination of two or more kinds, and a hydrophilic surfactant of not more than one half of the hydrophobic surfactant may be added, preferably 1% by weight or less. Step (III) Emulsifying or dispersing the dissolved and/or dispersed aqueous solution of the drug obtained in the step (I) (also referred to as the aqueous solution of the step (I)) and the dissolution and/or dispersion obtained in the step (Π). The organic solvent (hereinafter also referred to as the organic solvent of the step (II)) after the hydrophobic surfactant is mixed and emulsified. The aqueous solution of the step (I) may be added to the organic solvent of the step (Π), and the organic solvent of the step (II) may be added to the aqueous solution of the step (I), and the aqueous solution of the step (I) and the step (in a suitable manner) Π) The organic solvent is introduced into the emulsification tank while being heated and pressurized. The step (IV) of removing the solvent and/or dehydrating the desolvent and/or dehydrating may be carried out by a known method. For example, it may be carried out by vacuum freeze drying, drying under reduced pressure, nitrogen blowing or the like, but is not limited thereto. The method can be selected according to the purpose of the most appropriate drying method. Further, the "surfactant-drug complex" of the obtained S can be used not only for dispersing water in the fat but also for adsorbing it in a suitable carrier such as cerium oxide. Preparation of solid preparations such as powders, granules, tablets, capsules, and the like. 5-Bu 3. Next, each step in the manufacture of Hydros will be described in more detail. Step (I) Dissolving or dispersing a hydrophobic drug in an organic solvent to dissolve or disperse in an organic solvent to dissolve the drug in the organic solvent, and to efficiently dissolve and/or disperse the drug in the organic solvent, which can be heated Or pressurization" -37- 201113049 Step (11) Dissolution or dispersion of hydrophilic surfactants The surfactant used in the production of Hydros may be 8 or more, and the anionic, cationic, and Nonionic surfactant. As the anionic surfactant, a fatty acid soap, a cyclosapon, a long-chain alcohol sulfate, a polyoxyethylene alkylphenyl ether sulfate monoglyceride sulfate, a fatty acid monoalkylolamine sulfate, a salt, and α- can be used. Sulfated fatty acid salt, dialkyl sulfonated butyl octyl phenyl sulfonate, alkyl benzene sulfonate, polyoxyethyl ether phosphate, polyoxyethylene alkyl ether phosphate, laurel Wait. As the cationic surfactant, a long-chain primary amine salt, a quaternary ammonium salt, a dialkyldimethylammonium salt, an alkylpyrimidinium salt, a polyoxylamine, an alkylimidazolium or the like can be used. As the amphoteric surfactant, ruthenium-alkyl, /3-aminopropylalkyl/3-iminodipropionate or the like can be used. Water-soluble nonionic surfactants can be used with higher alcohols, alkyl phenyl vinyl oxides, fatty acid ethylene oxide alcohol fatty acid esters, ethylene oxygen additions, higher alkyl amino ethylene 'fatty acid amine vinyls Oxygen additives, ethylene oxide additional fatty acid esters of fats and oils, fatty acid esters of pentaerythritol, fatty acid amines of alkyl alcohol amines of polyhydric alcohols, and the like. Among the nonionic surfactants, for example, fatty acid esters of sorbitol and sorbitan, polyoxyethylene sorbate, polyethylene glycol fatty acid ester, and sucrose fatty acid ester are HLB-based, amphoteric formate. Salt, fatty basic sulfonate, polyoxyalkylene alkyl sulphate alkyl trimethyl ethinate, oxime - ethylene oxide addenda, polyoxygenate, glyceryl ether, alkyl can also be used Anhydride ester, polyoxyethylene-38- 201113049, polyethoxylated castoroil, polyethoxylated hydrogenated castoroil, polyoxyethylene polypropylene glycerol copolymer, glycerin fatty acid ester, polyglycerin fatty acid ester, and the like. The polyoxyethylene sorbitan fatty acid ester is preferably a polysorbate fatty acid ester 20, 40, 60, 80 or the like. The polyethylene glycol fatty acid ester is particularly preferably monolauric acid polyethylene glycerol or the like. The sucrose fatty acid esters are particularly sucrose palmitates (for example, trade name: P - 1 6 7 0, Mitsubishi Chemical Foods Co., Ltd.), sucrose stearate esters (for example, trade name: S-1670, Mitsubishi) Chemical foods (limited shares), sucrose laurates (for example, trade name: L-169S, Mitsubishi Chemical Foods Co., Ltd.) are preferred. Polyethoxylated castor oil is preferably a polyoxylated castor oil (Polyoxy 3 5 Castor oil, trade name: Cremophor EL or EL-P 'BASF Japan (share limited)). Polyethoxylated hydrogenated castor oil is particularly preferably polyoxyethylene hydrogenated castor oil 50 (Polyoxyethylene Hydrogenated Castor Oil 60). The polyoxyethylene polypropylene glycerol copolymer is preferably polyoxyethylene (160) polyoxypropylene (30) glycerol (trade name: Pluronic F-68, Asahi Chemical Industry Co., Ltd.). Polyglycerol fatty acid esters are preferably lauric acid polyglycerol (Decaglyn 1 - L, Shuguang Chemical (share limited)) and the like. One or two or more kinds of these hydrophilic surfactants may be contained. Further, it is preferable to use two or more kinds of hydrophobic surfactants in an amount of at most half of the hydrophilic surfactant, preferably 10% or less. -39- 201113049 Step (ΠΙ) Emulsify or disperse the dissolved and/or dispersed drug organic solvent obtained in the step (I) (hereinafter also referred to as the step (Ο organic solvent), and the dissolution and/or the step (Π) The aqueous solution (hereinafter also referred to as the aqueous solution of the step (II)) dispersed in the hydrophilic surfactant is mixed and emulsified. The organic solvent of the step (I) may be added to the aqueous solution of the step (II), or vice versa. The aqueous solution of the step (II) is added to the organic solvent of the step (I), and in an appropriate manner, the organic solvent of the step (I) and the aqueous solution of the step (II) are heated and pressurized to be introduced into the emulsifying tank. To manufacture any of the aforementioned LipoS. In the case of Hydros, it is preferable to use a film rotary high-speed mixer, a high-mixer, an impeller mixer, and an IPROS vacuum emulsifier. It is necessary to pay attention to the airtightness of the control valve shaft seal when high-speed stirring is performed while suppressing the sudden boiling of the gas pressure. The nature is very important, and a mechanical shaft seal or the like can be used. The step (IV) of removing the solvent and/or dehydrating the desolvent and/or dehydrating can be carried out by a known method. If it can be vacuum freeze-dried, dried under reduced pressure, nitrogen purged, etc., it is not limited to these methods, and the most appropriate drying method can be selected according to the purpose. In addition, the "surfactant-drug" of S is not only used. The nature of the active agent is such that the water is dispersed in the fat and adsorbed to a suitable carrier such as ceria, and can also be used in the manufacture of solid preparations such as powders, granules, tablets, capsules, etc. -40- 201113049 5-2. Solid-in-Water (S/W) Dissolving the drug, especially the hydrophobic poorly soluble drug, after dispersing or dissolving the tank a or dissolving the tank b, dissolving the surfactant in the dissolution tank b, In particular, after the hydrophilic surfactant is dissolved, it is emulsified in the emulsification tank c, and the drug-surfactant complex (Hydros) is dispersed by dehydration or de-solubilization, and the hydrophilic dispersion medium is dispersed (hydrophilicity). Solvent), S/W can be produced. Its structure is shown. 5-3 . Solid-in-Oil (S/Ο) When a drug-specific water-soluble drug is dissolved in the dissolution tank a, the hydrophobic surfactant is dissolved. In the dissolution tank a, or the special protection tank b After dissolving, it is emulsified in an emulsification tank (after emulsification, dehydration, and the production of a drug-surfactant complex (LipoS) is dispersed in pharmaceuticals, foods, and cosmetics that can be used in vegetable oils; ^ Dispersing medium (fat-soluble solvent) , Oil), and S/Ο can be produced. The damage is shown by 4. More specifically, the S/O is produced by a slit comprising the following steps: (A) Dissolving and/or dispersing the drug in water And a step of obtaining a solution and/or a dispersion in an active solvent such as an alcohol, and (B) dissolving or dissolving and/or dispersing the hydrophobic surfactant in the organic solvent by heating or the like. The dissolution angle f is dissolved in the dissolution tank a or the dissolution tank a: by using water or the like as shown in Fig. 3, at the same time, to dissolve the desolvent, and to form a hydrophilic liquid liquid by the fat-soluble method and / 41 - 201113049 or a step of dispersing liquid, (C) mixing, dissolving, or dispersing the solution and/or dispersion obtained in step (A) with the solution and/or dispersion obtained in step (B) ( D) subjecting the emulsion or dispersion obtained in step (C) to desolventization and/or dehydration step And (E) in step (D) obtained from a pharmaceutical surfactant system composite article 'dispersed in more than one of the vegetable oils and synthetic fat-soluble vehicle. And the steps (A) and (B) described above may be performed first or simultaneously. Further, the method of dissolving and dispersing the drug in the aqueous solution in the above step (A) is a method of improving the solubility using various methods. For example, a method of preparing a range in which solubility is high by using a pH adjuster, a method of adding a dissolution aid, heating or heating, and pressurization with an inert gas may be mentioned. Further, in the above method, the drug may be further dissolved or dispersed by adding the step (B) to maintain the fine powder state, or further, water may be added thereto for emulsification. Further, in the above step (B), the method of liquefying the hydrophobic surfactant by heating or the like may be a method of heating or heating and pressurizing with an inert gas. 5-4. Solid-in-Oil-in-Water (S/0/W) S/Ο manufactured by the above 5-3 can be produced by dispersing or dissolving in a hydrophilic solvent such as water. /0/W, its structure is shown in Figure 5. -42- 201113049 Further, S/0/W can be produced by a method of producing a step (F) in which the S/Ο obtained in the step (E) is dispersed in a hydrophilic solvent such as pure water or a buffer solution. . 5-5. S/W is produced by the production method consisting of the following steps. (a) a step of dissolving and/or dispersing a drug, particularly a hydrophobic poorly soluble drug, in an organic solvent to obtain a solution and/or a dispersion, and (b) subjecting the hydrophilic surfactant to a liquid state by heating or the like And dissolving, or dissolving and dispersing in a volatile hydrophilic solvent such as water or alcohol to obtain a solution of a solution and/or a dispersion, (c) a solution of the organic solvent obtained in the step (a) And/or the dispersion, the step of emulsification or dispersion by adding the solution and/or the dispersion obtained in the step (B), and the emulsion or dispersion obtained in the step (C) is subjected to the desolvent. And/or the step of dehydrating to obtain S, (e) can be produced by the production method in which the S obtained in the step (d) is dispersed in a hydrophilic solvent such as pure water or a buffer. And the above steps (a) and (b) may be carried out first, or may be carried out simultaneously in the above step (B), and the drug may be further dissolved or dispersed in a state of maintaining the fine powder, or further added to the organic solvent. It can also be emulsified. Further, in the step (B), a method of liquefying the hydrophilic surfactant by heating or the like may be a method of heating or heating and pressurizing with an inert gas. -43- 201113049 In addition to the above 5-2 to 5-5, any one or more steps of steps (A), (b), (C) and steps (A), (B), (C) may be performed, It is preferred to carry out the process of injecting a non-flammable gas. The gas to be injected is an inert gas, and is preferably 1 atmosphere or more, and more preferably 10 atmospheres or less. When the steps (B), (C) and the steps (A) and (C) are dissolved, dispersed or emulsified, it is preferred to inject a gas or a non-combustible gas in the gas phase portion above the liquid in the tank. The gas to be injected is an inert gas, and is preferably 1 atmosphere or more, and more preferably 10 atmospheres or less. Any one or two or more of nitrogen, carbonic acid, ammonia, and argon may be selected as the non-flammable gas. The desolvent and/or dehydration of the step (D) or the step (d) may be carried out by vacuum freeze drying, vacuum drying, microwave expansion drying, freeze pulverization drying, nitrogen blowing or the like. By this step, the drug can be obtained as a solid-state drug-surfactant complex product (S). In the present patent, the drug is defined as "the drug is encapsulated in a solid state" by the method of desolvent or/and dehydration. The surfactant used herein can be used for pharmaceuticals, foods, and cosmetics. For example, when a smaller drug-surfactant complex (S) is produced, the drug can be dispersed according to the purpose. After the hydrophilic solvent or the fat-soluble solvent, Hydros or LipoS is selected, and the type of the hydrophilic surfactant or the hydrophobic surfactant is selected. Types of Surfactants Used The types of surfactants are various depending on whether they are soluble or dispersible in a hydrophilic solvent or a fat-soluble solvent, and the purpose of the product. The present invention is not limited at all. In addition, -44- 201113049 can also be mixed with surfactants. The surfactant used in the drug-surfactant complex of the present invention is not particularly limited as long as it can be used for pharmaceuticals, food, or cosmetics, and examples thereof include an ionic or nonionic surfactant, and an ion. The surfactants are cationic, anionic, and amphoteric surfactants. You can choose one or more of these. The surfactant used in s/ο is a hydrophobic surfactant, and it is preferable to add a hydrophilic surfactant of less than half of the amount of the hydrophobic surfactant to 10% or less. The s/0/w obtained by redispersing the S/o-treated oil agent in the aqueous phase can be prepared by adding a hydrophilic surfactant to the aqueous phase. At this time, it is preferable to add a hydrophilic interface surfactant-half of a hydrophobic surfactant or a hydrophilic surfactant to 10% or less, irrespective of the oil phase or the aqueous phase. It is also possible to add a hydrophobic surfactant to the aqueous phase. The hydrophobic surfactant added to the aqueous phase is preferably less than or equal to 10% by weight of the hydrophilic surfactant. The surfactant used for S/W is a hydrophilic surfactant. It is preferred to add less than half of the hydrophobic surfactant of the hydrophilic surfactant to less than 10%. The hydrophilic surfactant may, for example, be an anionic, cationic, amphoteric or nonionic surfactant as described below. The anionic surfactant can be used as a fatty acid soap, a naphthenic acid soap, a long-chain alcohol sulfate vinegar, a polyoxyethylene alkyl phenyl ether sulfate salt, a fatty acid monoglyceride sulfate vinegar 'fatty acid monoalkyl alcohol amine sulfate Alkaline sulfonate, α-sulfonated fatty acid-45- 201113049 salt, dialkyl sulfonated succinate, polyoxyethylene octyl phenyl ether sulfonate, alkyl benzene sulfonate, polyoxyethylene An alkylphenyl ether phosphate salt, a polyoxyethylene alkyl ether phosphate salt, sodium lauryl sulfate or the like. As the cationic surfactant, a long-chain primary amine salt, an alkyltrimethylammonium salt, a dialkyldimethylammonium salt, an alkylpyrimidine salt, a polyoxyethylene alkylamine, an alkylimidazoline or the like can be used. As the amphoteric surfactant, an N-alkyl group, a cold-amino propionate, an N-alkyl-i-iminodipropionate or the like can be used. Hydrophilic nonionic surfactants can use higher alcohol ethylene oxide addenda, alkyl phenyl ethylene oxide addenda, fatty acid ethylene oxygen addenda, polyol fatty acid ester ethylene oxygen addenda, higher alkyl amino vinyl oxide Additives, fatty acid amino-vinyl oxide additions, ethylene oxide additions of fats and oils, glycerin fatty acid esters, fatty acid esters of pentaerythritol, alkyl ethers of polyhydric alcohols, fatty acid amines of alkyl alcohol amines, and the like. As the nonionic surfactant, fatty acid esters such as sorbitol and sorbitan, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, sucrose fatty acid esters, polyoxyethylene can also be used. Polyethoxylated castoroil, polyethoxylated hydrogenated castoroil, polyoxyethylene polypropylene glycerol copolymer, glycerin fatty acid ester, polyglycerin fatty acid ester, and the like. The polyoxyethylene sorbitan fatty acid ester is preferably a polysorbate fatty acid ester 20, 40, 60, 80 or the like. The polyethylene glycol fatty acid ester is particularly preferably monolauric acid polyethylene glycerol or the like. Sucrose fatty acid esters are particularly sucrose palmitates (for example, trade name: P-1 670, Mitsubishi Chemical Foods Co., Ltd.), sucrose stearate esters (for example, trade name: S - 1 6 7 0, Mitsubishi Chemical Corporation) Food (limited shares), sucrose laurate (for example, trade name: L-1 695 -46- 201113049, Mitsubishi Chemical Foods Co., Ltd.) is preferred. Polyethoxylated castor oil is particularly preferably polyoxyethylene castor oil (Polyoxy35 Castor Oil, trade name: Cremophor EL or EL-P, BASF Japan (share limited)). The polyethoxylated hydrogenated castor oil is preferably a polyoxyethylene hydrogenated castor oil 50 (Polyoxyethylene Hydrogenated Castor Oil 50) or a polyoxyethylene hydrogenated castor oil 60 (Polyoxyethylene Hydrogenated Castor Oil 60). The polyoxyethylene polypropylene eucalyptus copolymer is preferably polyoxyethylene (160) polyoxypropylene (30) glycerol (trade name: Pluronic F-68, Asahi Chemical Industry Co., Ltd.). Polyglycerol fatty acid esters are preferably lauric acid polyglycerol (Decaglyn 1 - L, Shuguang Chemical (share limited)) and the like. Examples of the hydrophobic surfactant include sucrose fatty acid esters such as sucrose stearate, sucrose palmitate, sucrose oleate, sucrose laurate, sucrose eucalate, and sucrose erucate, and sorbitan is hard. Sorbitan fatty acid esters such as ester esters, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, glyceryl monostearate A glycerin fatty acid ester such as an acid ester or a glycerol monooleate, a polyglycerol fatty acid ester such as a diisostearate diglyceride, a diisostearate diglyceride or a monoisostearate diglyceride. Two or more kinds of these surfactants can be used. The fat-soluble solvent to be used in the S/O or S/0/W of the present invention is not particularly limited as long as it is an organic solvent which can be used for pharmaceuticals, foods, or cosmetics, and examples thereof include vegetable oils and animal oils. Neutral lipids (monosubstituted-47-201113049, disubstituted, or trisubstituted glycerides), synthetic oils, and/or sterol derivatives. Specific examples of the vegetable oil include soybean oil, cotton oil, rapeseed oil, sesame oil, corn oil, peanut oil, safflower oil, sunflower oil, olive oil, jojoba oil, perilla oil, etc., and animal oils include tallow and pig. Oil, fish oil, etc., neutral fat can be cited as three oil essence, three linseed oil essence, three palm oil, tristearyl oil, three meat Xuanzhen oil or three arachidonic acid oil, etc., synthetic oil Examples thereof include isopropyl myristate, azone, hexane, toluene, chloroform, dichloromethane, ethyl acetate, dimethylacetamide, cyclohexane, acetone, dimethyl hydrazine, Examples of the sterol derivatives such as heptane and pentane include oleic acid cholesteryl ester, linolenic acid cholesteryl ester, cholesteryl cholesteryl ester, cholesteryl palmitate, and tri-arachidonic acid cholesteryl ester. These oils and fats can also be used in two or more types. Preferred oil components include glycerides and vegetable oils and animal oils which are mainly composed thereof. The utility model is preferably soybean oil, sesame oil, olive oil, squalene and squalane, and particularly preferably highly purified sesame oil and olive oil. The drug and the surfactant dose in the drug-surfactant complex (S) of the present invention vary depending on the type of hydrophilicity or hydrophobicity, but the weight ratio (surfactant/drug) relative to the surfactant of the drug is The range of 1 to 50 is better, the range of 2 to 30 is better, and the range of 5 to 20 is the best. 6. Formulation/Formulation According to the application of the present invention, the drug-48-201113049-based surfactant prepared according to the above 5. The complex (s) is made into S/O, S/W or s/o/w, and can be formulated as a compounding agent by changing the surface characteristics of the drug solvent and the gel, for example, water-soluble. The drug can be directly dispersed in the hydrophilic solvent, but in order to disperse the water-soluble drug and the water-soluble drug in the hydrophilic solvent, S/W or s/o/w can be performed. The hydrophobic poorly soluble drug may be directly dispersed in the fat-soluble solvent, but it may be s/odified and dispersed in a fat-soluble solvent. In addition, by making the drug into a drug-surfactant complex (S), a plurality of drugs which cannot be coexisted in a single solvent, for example, drugs which easily cause chemical reactions with each other, can be formed by the respective solvents. The drug-surfactant complex exists separately from each other and can be stored in a stable state, for example, without causing a reaction. In the present invention, the drug to be dispersed in the solvent is not limited to two kinds, and the application of the present invention includes dispersing two or more kinds of drugs in the same solvent. Further, as the drug to be used as a compounding agent, a drug disclosed in 2. a drug can be used. 6-1. One-lubrication of a water-soluble drug and a poorly soluble drug can be prepared by dissolving a water-soluble drug and a poorly soluble drug according to the above-mentioned 5. as a drug-surfactant complex (S), and then forming an S/ 0, S/W or S/O/W, as a compounding agent, can be formulated in one dosage form. Here, the water-soluble drug may, for example, be vitamin C, cysteine, hydroxyproline, aspartic acid Na, glutamic acid or arginine. The hydrophilic poorly soluble drug may, for example, be BCAA (leucine, isoxamine -49-201113049 acid, valine) which is called a branched amino acid. The hydrophobic poorly soluble drug may, for example, be CoQ10. The type of the drug is not limited to one type, and a plurality of types may be used. 6-1 -1. Specifically, when a water-soluble drug and a hydrophobic poorly soluble drug are dispersed in a hydrophilic solvent (for example, an aqueous solution) for formulation, it can be carried out in the following manner. (1) The water-soluble drug is maintained in water solubility, and the hydrophobic poorly soluble drug is made into Hydros and reconstituted as S/W, and can be dispersed in a hydrophilic solvent. (2) The water-soluble drug is made into S/0/W, and the hydrophobic poorly soluble drug can also be made into Hydros and reprocessed into S/W. The hydrophilic solvent is an aqueous solvent, pure water, a buffer solution or the like, and specific examples thereof include the following. For example, water for injection, physiological saline, phosphate buffer, Ringer's solution, acetate buffer, citrate buffer, borate buffer, tartaric acid buffer, Tris buffer, Macrogol 400, glycerin, propylene glycol, propanol, ethanol and These mixtures. 6-1 -2. When the water-soluble drug and the hydrophobic poorly soluble drug are dispersed in a fat-soluble solvent for formulation, the hydrophobic poorly soluble drug can be directly dispersed in the fat-soluble solvent, and the water-soluble drug can be prepared according to the above method. Formulated as LipoS or as S/0, it can be dispersed in a fat-soluble solvent. The fat-soluble solvent is not particularly limited as long as it is an organic solvent which can be used for pharmaceuticals, foods, or cosmetics, and examples thereof include vegetable oils, animal oils, and neutral lipids (monosubstituted, disubstituted, or trisubstituted glycerides). ) -50- 201113049 , synthetic oils and fats, and / or sterol derivatives. Specific examples of the vegetable oil include soybean oil, cotton oil, rapeseed oil, sesame oil, corn oil, peanut oil, safflower oil, sunflower oil, olive oil, jojoba oil, avocado oil, perilla oil, etc., and animal oil can be mentioned. For the tallow, lard, fish oil, etc., the neutral fat can be cited as three oil essence, three linseed oil essence, three palm oil essence, tristearate oil essence, three meat simmer oil or three arachidonic acid oil, etc. The synthetic fats and oils include meat isopropyl isopropylate, azone, hexane, toluene, chloroform, dichloromethane, ethyl acetate, dimethylacetamide, cyclohexane, acetone, and dimethyl. Examples of the sterol derivatives such as ketamine, heptane, and pentane include cholesteryl oleate, cholesteryl linolenate, cholesterol citrate, cholesteryl palmitate, and cholesterol ester of arachidonate. These oils and fats can also be used in two or more types. Preferred oil components include glycerides and vegetable oils and animal oils which are mainly composed thereof. The utility model is preferably soybean oil, sesame oil, olive oil, squalene and squalane, and particularly preferably highly purified sesame oil and olive oil. Further, the above-mentioned drug may be dispersed in a soft capsule and a hard capsule by dispersing a fat-soluble solvent, and the soft capsule and the hard capsule may be packaged in a bubble wrap. 6-1 -3. When a water-soluble drug and a hydrophilic poorly soluble drug are dispersed in a fat-soluble solvent, they can be made into LipoS, and can be dispersed in a fat-soluble solvent by dispersing in an oil phase to form S/Ο. in. As the fat-soluble solvent, a fat-soluble solvent as described in the above 6-1-2 can be used. -51 - 201113049 6-1 -4. When the water-soluble drug and the hydrophilic poorly soluble drug are dispersed in the hydrophilic solvent, the hydrophilic poorly soluble drug can be made into LipoS, and then dispersed in the oil phase to form S/Ο. It is then dispersed in the aqueous phase to make s/0/W, which can be dispersed in a hydrophilic solvent. As the hydrophilic solvent, a hydrophilic solvent as described in the above 6-1-1 can be used. 6-1 -5. When a water-soluble drug and a poorly soluble drug are used in a solid or gel state, other solid components or gel components may be mixed with Hydros and/or L i ρ 〇 S. Other solid components or gel components include carboxymethylcellulose Na, sodium alginate, carrageenan, pectin, agar, lanolin, glucomannan, polyvinylpyrrolidone, carboxyvinyl polymer, and jaundice. Glue, acrylamide, polyvinylidene alcohol, and the like. The hydrophilic poorly soluble drug can also be made into LipoS by the effect of gelling the substrate, and can be dispersed in the aqueous gel. 6-2. For example, a chemical reaction in which a chemical reaction occurs in a solvent and a plurality of drugs which cannot coexist is contained. The chemical reaction system referred to in the present invention includes any chemical reaction which affects a drug, and for example, The redox reaction, the chelate reaction, the anion-cation reaction, and the addition reaction 'amine carbonyl reaction are not limited to these reactions. 6-2-1. Compounds causing redox reaction-52- 201113049 In combination with a compounding agent, it is impossible to mix an oxidizing drug with a reducing drug in a dosage form, but according to the patent technology may. Drugs having an oxidizing action include, for example, Miconazole Nitrate, Isosorbide Dinitrate, Naphazoline Nitrate, and the like. Drugs having a reducing action are, for example, vitamin C, cysteine 'acetaminos' cysteine, cinnamaldehyde, vitamin E, 8 carotene, folic acid, uric acid, ubiquinone, hexadecanepentaenoate, bran Amino sulfur, sodium sulfite, and the like. 6-2-2. The combination of an anionic drug and a cationic drug with a complexing agent cannot match an acidic drug (an anionic drug) with a basic drug (a cationic drug) in a dosage form, but according to the patent technology It becomes possible. Examples of the anionic drugs include nucleic acid drugs such as adenosine triphosphate, RN A and DN A, valproic acid, dipropyl sulfonamide benzoic acid, penicillin, indomethacin, biphenylacetic acid, and Huafa Warfarin, salicylic acid, aspirin, phenobarbital, sodium chamomile sulphate, sulphate, (Alprostadil), Amlexanox, glycyrrhizic acid, etc. Examples of the cation-based drug include antibiotics such as doxorubicin, olotadine, dopamine, benidipine, and mitoironomicin, and stomach. Domperidone, Venorelbine, Tropisetron 'Cimetidine', Plymouth-53-201113049 (Procainamide), tetracycline, Imipramine , amphetamine, meperidine, etc. 6-2-3. The chelating agent is a combination of complexing agents, and the drug which can cause the metal ion exchange reaction, which is a complex compound (chelate), cannot be compounded in a dosage form, but according to the patent technology It becomes possible. For example, aluminum hydroxide and neonaphthylquinones, metal chelate drugs (Ca-2Na-EDTA, diisopropyl alcohol, Deferoxamine, and metal ion-containing drugs (Cyanocobalamin, A) Methylcobalamin, Cisplatin Platinum Complex Anticancer, Aceglutamide Aluminum. Further, Cisplatin Platinum Complex Anticancer (Cisplatin, Carboplatin, Nedaplatin, Oxaliplatin, etc.), and physiological saline and forest When a liquid containing Na ions and Ca ions is combined with a Grignard solution, the ligand exchange is caused, but the surfactant can be compounded by the surfactant of the present patent. 6-2-4. Amine carbonyl reaction The combination of the complexing agent, because the amino acid and the amine-containing drug may cause a so-called amine carbonyl reaction with the saccharide and the aldehyde-containing drug, and cannot be combined, but it becomes possible according to the patent technology. Amino acid and amine-containing The base of the drug can be exemplified by various amino acids, interferons, human growth hormone, granule growth factor, insulin, Calcitonin Salmon, other protein peptides, dopamine, acesulfame Oxazole-54- 201113049, allantoin, norepinephrine, aminophenanthrene, etc. In addition, saccharides and aldehyde-containing drugs include glucose 'lactose, sucrose, acemannolactone (Aceglatone), and three-part glycoside (Tribenoside) ), adenosine (Vidarabine), etc. 6-2-5. Formulation of the above-mentioned multiple drugs that produce a chemical reaction, each of which can be classified as a water-soluble drug, a hydrophilic poorly soluble drug, and hydrophobically poorly soluble. When the above plurality of drugs are all water-soluble drugs, (a) each drug is made into a drug-surfactant complex (LipoS) and dispersed in the oil phase (Oil) to become Solid-iii- The type of Oil (S/0) is dispersed in the preparation of the fat-soluble drug, or is (B) the drug made by each drug-the surfactant complex (LipoS) and dispersed in the oil phase (Oil) -in-Oil (S/Ο), which is further dispersed in the aqueous phase, & Solid-in-Oi 1-in-Water (S/0/W), and is a preparation dispersed in a hydrophilic solvent. When the above plurality of drugs are all hydrophobic poorly soluble drugs, each drug is made into a drug-interface The compound complex (Hydros) is dispersed in the Solid-in-Water (S/W) form after the water phase, and becomes a formulation dispersed in a hydrophilic solvent. The above plurality of drugs are all hydrophilic and poorly soluble. In the case of drugs, the drug-surfactant complex (LipoS) of each drug is dispersed in the oil phase (ΟΠ) after Solid-in-Oil (S/Ο), and then dispersed in the water phase -55- 201113049
Solid-in-Oil-in-Water ( S/0/W)之型態，成爲分散 性溶媒之製劑。 另外，上述之複數種藥物均爲親水性難溶性藥 散於水性凝膠時，可以每一種藥物之藥物-界面活 合體（Solid)並分散於水相（Water)後之Solid-i (S/W )之型態，分散於水性凝膠後進行製劑化。 藥物-界面活性劑複合體於任一情形均可如上 藥物-界面活性劑複合體所記載之方法進行製造。 另外，親水性溶媒及脂溶性溶媒可使用記載於 1-1 及 6-1-2 者。 6-3.添加劑，劑型 本發明之使相異物性藥物一劑型化之製劑（配 爲液狀或懸濁狀時，可藉由使可用於醫藥品、食品 品等之乳糖及二氧化矽凝膠、結晶纖維素、澱粉等 將其吸收，而可進行粉體化。 於本發明之使相異物性藥物一劑型化之製劑（ )中所使用之安定化劑等添加劑，可自醫藥品、食 妝品等所使用之添加劑中選擇使用，例如牛血清白 雞蛋白蛋白、牛奶酪蛋白等蛋白質，或麥芽糖、鹿 藻糖等糖類，肝素、幾丁聚醣 '海藻酸鹽、聚丙稀 甲烯酸、羧甲基纖維素等多醣類等，考慮藥物之物 性等，因應目的自由選擇爲佳，本發明並未因該等 有所限定。 :於親水 丨物且分 性劑複 n-Water :述5 .之 ‘上述6- 合劑） 、化妝 添加物 配合劑 品、化 蛋白、 糖、海 酸、聚 性及相 例示而 -56- 201113049 所使用之添加劑’爲使例如s/o、S/W、S/0/W安定化 ，可舉出保護膠體劑及增黏劑。保護膠體劑可舉出胺基酸 、蛋白質、糖類及多醣類等。增黏劑可舉出例如羧甲基纖 維素鈉、海藻酸鈉、玻尿酸鈉、葡聚糖等水溶性多糖類等 。油性的增黏劑可舉出各種脂肪酸及油脂類等。 保存劑可舉出苯甲酸甲酯、苯甲酸乙酯等烷基苯甲酸 酯等。 無痛化劑可舉出例如苯甲醇、鹽酸利多卡因、氯代丁 醇等。 pH調整劑可舉出例如鹽酸、醋酸、氫氧化鈉或各種緩 衝劑等。 6-4.本案配合劑之用途 本發明之使相異物性藥物一劑型化之製劑（配合劑） ，可直接或與其他成份一同作爲醫藥品使用。前述之醫藥 品可舉出例如注射劑、內服劑、外用劑、點眼劑、齒科用 劑，進而可舉出使難溶性藥物成爲可溶化性之注射劑、點 眼劑、散劑、顆粒劑、錠劑、膠囊劑、液劑、凝膠劑等內 服劑，泥罨劑及藥布等貼付劑，軟膏劑、乳霜劑、乳液劑 、液劑、噴霧劑等外用劑及齒科用劑等，該等劑型之製造 可以周知之方法進行，但並未因此而使本發明有任何限制 〇 本發明之使相異物性藥物一劑型化之製劑（配合劑） ，可直接或與其他成份一同作爲食品使用。前述之食品可 -57- 201113049 舉出例如一般食品、食品添加物、牛乳、乳飲料、起司、 優格等乳製品、加工乳、偏好性飮料、調味料、香辛料、 清涼飲料水、加工飲料、功能性食品、被稱作特定保健用 食品•營養功能食品之保健功能食品、特別用途食品等， 但本發明並未因此而使有任何限制。 進而使用本發明配合劑之化妝品可舉出例如粉底液、 面膜、乳霜、乳液、化妝水、精華液、卸妝液'口紅、唇 線筆、唇蜜、睫毛膏、眼影、眼線筆、眉粉筆、腮紅等， 但本發明並未因此而使有任何限制。 7.以藥物-界面活性劑複合體之藥物掩蔽或防臭方法， 或藥物之保存安定化 本發明案中亦包含將欠缺於溶媒中具安定性之藥物， 或呈現異臭或不愉快氣味之藥物，藉由將其根據前述5.之 記載製爲藥物-界面活性劑複合體，使其增加於溶媒中之 安定性之方法，或掩蔽、防臭之方法。 藥物係可舉出如上述2.中所揭示之藥物。特別掩蔽或 防臭方法於如半胱胺酸等氣味強烈的藥物，及BCAA (分 支鏈胺基酸或分歧鏈胺基酸）等呈現苦澀味等不愉快氣味 之藥物爲佳。使用安定化方法之藥劑可舉出例如於溶媒中 旋即溶解之藥物，或爲被氧化或被還原之藥劑，具體而言 可舉出維他命C或其衍生物等。 溶媒可使用記載於上述6之親水性溶媒或脂溶性溶媒 -58- 201113049 以下例示其製造力與實施例，但本發明並未因此而使 有任何限制。 [實施例] [製造例1]製造藥物一界面活性劑複合體（S) (水溶性藥物之脂溶性化，以下稱作Lipos ) 使7.9g之蔗糖脂肪酸酯（ER-290 )完全溶解於75g之 己烷中。另外再於50g純水中加入0.1 g之檸檬酸’及2g之 抗壞血酸磷酸酯鎂（維他命C衍生物，以下略稱作VC· PMg )並使其完全溶解。再將此水溶液加入前述之溶解蔗 糖脂肪酸酯（ER-290 )後之己烷溶液中，使用均質機以 20000rpm，5min進行乳化。進行乳化後再以蒸發機去除己 烷相。去除溶媒後，以-45 °C冷凍並進行冷凍乾燥處理’ 藉由完全去除溶媒可調製VC· PMg —界面活性劑複合體（ VC · PMg- LipoS )。 [製造例2]製造藥物-界面活性劑複合體（S ) (難溶性藥物之親水化，以下稱作Hydros ) 使120g之月桂硫酸鈉（SLS)完全溶解於1 200g之純水 ，再使用靜止型攪拌機以1 500rpm進行攪拌，同時加入使 40g泛醌（以下稱作CoQlO )溶解於120g之己烷後之溶液。 將該溶液以〇. 1 M m之疏水性膜進行膜乳化，而進行乳化後 ，以_4 5°C冷凍並進行冷凍乾燥處理，可調製CoQlO-界面 活性劑複合體（CoQlO - Hydros)。 -59- 201113049 [製造例3]製造藥物-界面活性劑複合體（s ) (難溶性藥物之掩蔽，BCAA/LipoS) 將溶解於液溫60°C、100g純水中之1.907g之白胺酸、 0.952g之異白胺酸、l.i44g之纈胺酸等3種疏水性胺基酸（ 分支鏈胺基酸，以下稱作BCAA)之溶液，加入使12g之蔗 糖脂肪酸酯（ER-290 )完全溶解於150g之正己烷之溶液中 ’以均質機型高攪拌（20000rpm )後，調製爲W/0型乳糜 溶液。再將該乳糜溶液藉由經一夜冷凍乾燥後，調製爲 BCAA —界面活性劑複合體。 [製造例 4]製造 Solid-in-Water ( S/W) (難溶性藥物之掩蔽，BCAA/LipoS) 將於製造例2中難溶性藥物之CoQ 10的表面，改變爲親 水性後之5g之CoQl 〇 - Hydros，完全溶解於45g之純水中 ，製造 S/W化 CoQl 〇。 [製造例5]製造 Solid-in-Oil ( S/0) 相對於製造例1中所得之0.5g之VC · PMg-LipoS，加入 9.5g之肉豈蔻酸異丙酯，藉由進行溶解可得S/Ο化之VC . P M g。 [製造例 6]製造 Solid-in-Oil-in-Water ( S/O/W) 藉由將製造例5中所製造之lg之S/Ο化VC · PMg，分散 -60- 201113049 、溶解於9 g之0.1 %聚氧乙烯氫化蓖麻油6 0水溶液中，製造 S/0/W化之 VC · PMg。 [製造例7]製造CoQlO - Hydros錠劑 將製造例2所製造之1200g之CoQlO — Hydros ’與9〇〇g 之L-天門冬胺酸鈉、900g之L-麩醯胺酸、900g之L-精胺酸 進行混合，再加入312g之打錠助劑，以網目爲20之粉碎式 造粒機過篩。再加入1560g之結晶纖維素’ 9672g之 Perfiller -102並進行混合，接著再力日入156g之蔗糖一酯’ 進行混合及打錠後，得CoQlO-HydroS錠劑。 [製造例8]製造VC· PMg — LipoS乳霜劑 量取98g之Plastibase、32g之山俞醇、16g之—氧化砂 油、20g之角鯊烷，使用靜止型攪拌機以l 500rPm進行攪泮 ，同時加熱至90。(：，並使其完全溶解。加熱後將攪拌速度 固定在lOOOrpm，並冷卻至5CTC。此時加入已溶解l〇g之 VC. PMg-LipoS之30 g之椰子油，再加入4S之滑石及0.2g 之焦亞硫酸鈉，以2500rpm攪拌1〇分鐘。冷卻至4〇°C後’ 充塡於鋁製軟管中，得VC· PMg — LipoS乳霜劑（S/O)。 [製造例9]製造VC. PMg - LipoS油 製造例1所製造之lg之VC. PMg - LipoS’加入9g之椰 子油並進行攪拌且使其溶解後，分裝於專用之玻璃製化妝 瓶，製造成 VC· PMg-LipoS 油（S/O)。 -61 - 201113049 [製造例10]製造BCAA - LipoS凝膠 於容器中加入64g之純水，再加入O.ig之檸檬酸並進 行攪拌且使其完全溶解。投入10g之山梨醇酐脂肪酸酯及 於製造例3所製造之16gBCAA - LipoS，以I500rpm進行攪 拌5min，再加熱至60°C。 另外使0.54g之卡拉膠、0.18g之黃耆膠、〇.〇9g之長角 豆膠均勻分散於9g之濃甘油後，投入上述之溶液中，待全 量投入後’將攪拌速度昇至5000rpm，並加熱至溫度爲85 °C。待加熱後將攪拌速度固定於3000rPm，接著再投入 〇.〇9g之羥基苯甲酸丙酯，進行30分鐘加熱殺菌。保持攪 拌速度爲3 000rPm，並使溫度下降至60 °C ，得BCAA -LipoS凝膠劑（S/W ) » [製造例11]製造BCAA — LipoS油 於製造例3所製造之16gBCAA-LipoS中，加入34g中 鏈脂肪酸三甘油脂，進行攪拌溶解後，以液體、黏體塡充 機進行塡充，製造成BCAA - LipoS油（S/Ο)。 [製造例1 2]製造藥物-界面活性劑複合體（S ) (水溶性藥物之脂溶性化，LipoS之製造例） 使18g之蔗糖脂肪酸酯（ER-290 )完全溶解於75g之己 烷中。另外再於50g純水中加入2g之VC . PMg並使其完全 溶解。再將此水溶液加入前述之溶解蔗糖脂肪酸醋（ER- -62- 201113049 290)後之己烷溶液中’使用均質機以2〇〇00 rPm’ 5min進 行乳化。進行乳化後再以蒸發機去除己烷相。去除溶媒後 ，以-45 °C冷凍並進行冷凍乾燥處理，藉由完全去除溶媒 可調製成VC· PMg —界面活性劑複合體（VC· PMg — LipoS ) ° [製造例13] (水溶性藥物之脂溶性化，LipoS油之製造例） 於90g之蔗糖脂肪酸酯（ER-29〇)中加入3〇g之中鏈脂 肪酸三甘油脂，攪拌至使其均勻爲止。以該溶液爲界面活 性劑油溶液。再以其他容器，使1 〇g L-半胱胺酸溶解於 7 〇 g之純水中，再將該水溶液加入前述之界面活性劑油溶 液。使用均質機以20000rpm，5min進行乳化。進行乳化後 再以-45 °C進行冷凍乾燥處理，藉由完全去除水分，調製 成半胱胺酸—界面活性劑複合體（LipoS)之（S/Ο)。 [製造例14] (疏水性難溶性藥物之親水性化，H y d r 〇 S之製造例） 使2g之泛醌（CoQlO)完全溶解於75g之己烷中。另外 於50g之純水中加入18gSLS並使其完全溶解。將該水溶液 加入前述之已溶解CoQlO之己烷溶液中，使用均質機以 20000rpm，5分鐘進行乳化。進行乳化後再以蒸發機去除 己烷相。去除溶媒後，以-45 °C冷凍進行冷凍乾燥處理， 藉由完全去除溶媒，可調製成CoQlO—界面活性劑複合體 -63- 201113049 (CoQlO — HydroS)。 [製造例l5] (水溶性藥物之脂溶性化，LipoS之製造例） 將45g之蔗糖脂肪酸酯（ER-290 )加入3 00g之己烷並 使其完全溶解。另外再於3 0g純水中加入5g之羥脯胺酸（ 以下簡稱HP)並使其完全溶解。再將此水溶液加入前述之 溶解蔗糖脂肪酸酯（ER-290 )後之己烷溶液中’使用均質 機以20000rpm，5分鐘進行乳化。進行乳化後再以蒸發機 去除己烷相。去除溶媒後，以-45 °C冷凍並進行冷凍乾燥 處理，藉由完全去除溶媒可調製成HP—界面活性劑複合體 (HP - LipoS )。 [製造例 16]製造 Solid-in-Oil ( S/0) 相對於製造例1中所得之〇.5g之VC· PMg — LipoS’加 入9.5g之芝麻油，藉由進行溶解可得S/Ο化之VC· PMg。 [製造例 17]製造 Solid-in-Oil ( S/O) 相對於製造例15中所得之〇.5g之HP - LipoS ’加入 9.5g之芝麻油，藉由進行溶解可得S/O化之HP。 [製造例 18]製造 Solid-in-Oil ( S/O) 相對於製造例1中所得之0.5 g之VC · PMg — LipoS，及 製造例1 5中所得之0.5g之HP — LipoS ’加入9g之芝麻油， -64- 201113049 藉由進行溶解可得S/Ο化之VC· PMg與S/O化之HP之混合 液0 [實施例1] (藉由s/ο之藥物安定化） 使用製造例5所製造之s/o化VC · PMg，檢視於室溫下 2年期間的長期安定性。陽性對照係使用未進行S/O化之 VC . PMg溶液，陰性對照係使用使用於S/Ο化之分散媒。 圖6之照片係於室溫下經保存2年後者’自面向圖片左端開 始分別爲S/Ο化VC. PMg、陽性對照之VC· PMg溶液、陰 性對照之S/Ο之分散媒（〇 ) 。VC · PMg溶液出現經時之變 褐變化，然而S/0化VC · PMg與分散媒於相同之狀態下’ 完全未產生變褐，顯示極爲安定。 [實施例2] (藉由S/Ο之增加藥物之皮膚吸收性） 使用製造例5所製造之S/Ο化VC· PMg’檢視皮膚吸收 性之增加。 陽性對照係使用將維他命C含量調整爲相同量之1 〇mg /mL抗壞血酸棕櫚酯磷酸三鈉（維他命C衍生物，以下簡 稱作APPS )水溶液，陰性對照係使用未進行S/Ο化之調整 爲相同量之僅含有V C · P M g的水溶液。以該等檢體對醚麻 醉下之小鼠腹部，每lcm2塗佈50 # L。4小時後，將塗佈部 位之皮膚組織剝下，經量秤後，使用聯胺比色法定量維他 -65- 201113049 命C之含量。圖7中縱軸係表示相對於小鼠皮膚組織重量g 之維他命C之含量（/zg) ’橫軸由正面左端開始分別爲 S/Ο化VC · PMg塗佈群、VC · PMg塗佈群（陰性對照群） 、及APPS塗佈群（陽性對照群）。S/Ο化之VC · PMg群與 僅投藥VC· PMg之群相比，皮膚中維他命C之含量明顯上 升。另外與維他命C衍生物之APPS相比，亦爲相同或是增 加。藉由S / 0化，可明顯提升維他命C之皮膚吸收性。另外 由APPS之安定性較不佳，安定性優異之S/O化VC · PMg明 顯居於優勢。 [實施例3 ] (藉由藥物-界面活性劑複合體之營養因子的苦味及澀味 之掩蔽） 使用製造例1〇所製造之支鏈胺基酸，實施正常試驗者 8名之官能實驗。 官能實驗係使用1) s化支鏈胺基酸，及2)等量的支 鏈胺基酸與界面活性劑之混合物此2種檢體進行。此處爲 避免支鏈胺基酸及添加物特有的氣味對味覺判斷的影響， 於該等檢體中均添加〇·〇】重量％之檸檬油。官能實驗以自 檢體編號的規則性無法推測檢體之方式，進行隨機編號後 ，分別給予受試者經秤量〇 . 5 g之檢體，並賦予順位。本官 能實驗進行2次，其結果如表1所示。根據該結果可有意義 地改善因進行S化而產生的苦澀味等不愉快的口感。 -66- 201113049 表1 苦澀味 A B C D E F G Η 1揮1次 te yi w 弱 弱 Μ jw\ 弱 Αητ IIU* /»Ν\ ίΕ 弱 2揮1次 強 強 強 強 強 強 強 強 1揮2次 無 弱 弱 弱 弱 Ατττ. im： Μ j \ \\ 弱 2)第2次 強 強 強 強 強 強 強 強 [實施例4] (因水溶性藥物之脂溶性化之與疏水性藥物的一劑型化） 將製造例12所調製之5gVC · PMg —界面活性劑複合體 (VC · PMg - LipoS )，與 〇.5g之維他命 E(VE)加入 lkg 橄欖油中，使用攪拌子進行分散可得一澄清均勻之溶解液 。使用旋轉型軟膠囊形成塡充機，將該均勻溶解液以定量 之〇.4g分別塡充成形，製成高含量均一性之含VC· PMg、 VE之軟膠囊劑。軟膠囊之形狀除一般的長橢圓狀之外，亦 可以旋扭狀進行製造。使用同樣形式的軟膠囊形成塡充機 ，以定量之0.1 g分別塡充成形，製成高含量均一性之含VC • PMg、VE之軟膠囊劑。反之，直接將〇.5gVC. PMg及 〇.5gVE，分散於含有4.5g之蔗糖脂肪酸酯（ER-290 )之 lkg橄欖油中，不會形成澄清，亦觀察到VC· PMg於液體 中以懸濁狀態呈現浮游狀態。而將其靜置時會觀察到沉澱 物，無法形成塡充爲軟膠囊。製成後之軟膠囊可藉由塑膠 薄膜及鋁製薄膜所形成之易撕型氣泡包裝進行包裝，使軟 膠囊即便硬度柔軟但仍容易取出，並且可製成清潔的，且 易於運送攜帶方便之製品。軟膠囊亦可以擠壓型氣泡包裝 進行包裝。如此，藉由對水溶性營養因子之VC . PMg進行 -67- 201113049 VC · PMg —界面活性劑複合體（VC . PMg — LipoS )化’ 可使疏水性難溶性營養因子之VE均勻地分散或溶解於植物 油中。 [實施例5] (使CoQlO- Hydros微分散•溶解於離子電滲用含藥電極 凝膠水溶液之S/W之實施例） 於0.3%檸檬酸緩衝溶液（PH6 )中溶解〇.2g之The form of Solid-in-Oil-in-Water (S/0/W) is a formulation of a dispersible solvent. In addition, when the above plurality of drugs are all hydrophilic insoluble drugs dispersed in the aqueous gel, the drug-interface complex of each drug can be dissolved and dispersed in the water phase (Solid-i) (S/ The form of W) is dispersed in a water-based gel and formulated. The drug-surfactant complex can be produced by any of the methods described above for the drug-surfactant complex. Further, as the hydrophilic solvent and the fat-soluble solvent, those described in 1-1 and 6-1-2 can be used. 6-3. Additive, dosage form The preparation for dissolving the foreign substance drug of the present invention (when it is in liquid or suspended form, it can be condensed by using lactose and cerium oxide which can be used for medicines, foods, etc. Glue, crystalline cellulose, starch, etc. are absorbed and can be powdered. The additives such as stabilizers used in the preparation of the dissimilar drug of the present invention can be used for pharmaceutical products, It is used for additives such as food cosmetics, such as bovine serum white egg white protein, bovine cheese protein, or sugars such as maltose and trehalose, heparin, chitosan 'alginate, and polypropylene. It is preferable to select a polysaccharide such as an acid or a carboxymethylcellulose in consideration of the physical properties of the drug, etc., and the present invention is not limited by the above. The present invention is not limited by the above: in the hydrophilic sputum and the complexing agent complex n-Water : The above-mentioned '6-mixtures', cosmetic supplements, chemical proteins, sugars, sea acids, polycondensation, and phase-expressing -56-201113049 additives used to make, for example, s/o, S /W, S/0/W stability, can be mentioned as protective glue Agent and tackifier. Examples of the protective colloid include amino acids, proteins, sugars, and polysaccharides. Examples of the tackifier include water-soluble polysaccharides such as sodium carboxymethylcellulose, sodium alginate, sodium hyaluronate, and dextran. Examples of the oily tackifier include various fatty acids and fats and oils. The preservative may, for example, be an alkyl benzoate such as methyl benzoate or ethyl benzoate. The pain-relieving agent may, for example, be benzyl alcohol, lidocaine hydrochloride or chlorobutanol. The pH adjuster may, for example, be hydrochloric acid, acetic acid, sodium hydroxide or various buffers. 6-4. Use of the compounding agent in the present invention The preparation (compounding agent) for dissolving the foreign body-releasing drug of the present invention can be used as a pharmaceutical product directly or in combination with other components. Examples of the pharmaceutical preparations include injections, internal preparations, external preparations, eye drops, and dental preparations, and further, injections, eye drops, powders, granules, and ingots which make the poorly soluble drug soluble. Oral agents such as agents, capsules, liquids, gels, etc., sticking agents such as lozenges and medicated cloths, external preparations such as ointments, creams, lotions, liquids, sprays, and dental agents, etc. The preparation of the dosage forms can be carried out by a known method, but the present invention is not limited thereto. The preparation (complexing agent) for dissolving the foreign body drug of the present invention can be used as a food directly or together with other ingredients. use. The aforementioned food can be -57-201113049, for example, general foods, food additives, cow's milk, milk drinks, cheese, yogurt, processed milk, processed milk, seasonings, spices, refreshing drinks, processed beverages Functional foods, health-care functional foods, special-purpose foods, etc., which are called specific health foods, nutritionally functional foods, etc., are not limited by the present invention. Further, the cosmetic using the compounding agent of the present invention may, for example, be a liquid foundation, a mask, a cream, an emulsion, a lotion, an essence, a make-up remover, a lipstick, a lip liner, a lip gloss, a mascara, an eye shadow, an eyeliner, and a eyebrow chalk. , blush, etc., but the invention is not limited thereby. 7. Drug masking or deodorizing method of drug-surfactant complex, or preservation of drug. The present invention also includes a drug which is lacking in stability in a solvent, or a drug exhibiting an odor or an unpleasant odor. A method of adding a drug-surfactant complex to the stability of a solvent according to the above-mentioned 5., or a method of masking or deodorizing. The drug system can be exemplified by the drug disclosed in the above 2. A special masking or deodorizing method is preferably a drug which is strong in odor such as cysteic acid, and an unpleasant odor such as BCAA (particial branched chain amino acid or divalent chain amino acid) which exhibits a bitter taste. The agent which uses the stabilization method may, for example, be a drug which is dissolved immediately in a solvent, or a drug which is oxidized or reduced, and specific examples thereof include vitamin C or a derivative thereof. The solvent can be exemplified by the above-described 6 hydrophilic solvent or fat-soluble solvent -58-201113049, and the production power and examples thereof are exemplified, but the present invention is not limited thereto. [Examples] [Production Example 1] Production of a drug-surfactant complex (S) (lipophilization of a water-soluble drug, hereinafter referred to as Lipos) 7.9 g of sucrose fatty acid ester (ER-290) was completely dissolved in 75 g of hexane. Further, 0.1 g of citric acid' and 2 g of magnesium ascorbyl phosphate (vitamin C derivative, hereinafter abbreviated as VC·PMg) were further added to 50 g of pure water and completely dissolved. Further, this aqueous solution was added to the above-mentioned hexane solution in which sucrose fatty acid ester (ER-290) was dissolved, and emulsified at 20000 rpm for 5 minutes using a homogenizer. After emulsification, the hexane phase is removed by an evaporator. After removing the solvent, it was frozen at -45 °C and subjected to freeze-drying treatment. The VC·PMg-surfactant complex (VC·PMg-LipoS) was prepared by completely removing the solvent. [Production Example 2] Production of a drug-surfactant complex (S) (hydrophilization of a poorly soluble drug, hereinafter referred to as Hydros) 120 g of sodium lauryl sulfate (SLS) was completely dissolved in 1 200 g of pure water, and then used still. The stirrer was stirred at 1,500 rpm while adding a solution obtained by dissolving 40 g of ubiquinone (hereinafter referred to as CoQlO) in 120 g of hexane. This solution was subjected to membrane emulsification with a hydrophobic membrane of M1 M m, and after emulsification, it was frozen at _45 ° C and lyophilized to prepare a CoQlO-surfactant complex (CoQlO - Hydros). -59- 201113049 [Production Example 3] Manufacturing drug-surfactant complex (s) (masking of poorly soluble drug, BCAA/LipoS) 1.907 g of white amine dissolved in 100 g of pure water at a liquid temperature of 60 ° C A solution of three kinds of hydrophobic amino acids (branched chain amino acids (hereinafter referred to as BCAA) such as acid, 0.952 g of isoleucine, and 1.4 g of proline, and 12 g of sucrose fatty acid ester (ER) -290) Completely dissolved in a solution of 150 g of n-hexane. After stirring with a homogenizer type (20000 rpm), a W/0 type chyle solution was prepared. The chyle solution was further lyophilized overnight to prepare a BCAA-surfactant complex. [Manufacturing Example 4] Production of Solid-in-Water (S/W) (masking of poorly soluble drug, BCAA/LipoS) The surface of CoQ 10 of the poorly soluble drug in Production Example 2 was changed to 5 g after hydrophilicity. CoQl® Hydros, completely dissolved in 45 g of pure water, produces S/W CoQl®. [Production Example 5] Production of Solid-in-Oil (S/0) With respect to 0.5 g of VC·PMg-LipoS obtained in Production Example 1, 9.5 g of isopropyl myristate was added, and dissolution was carried out. Get S/Ο化的VC. PM g. [Manufacturing Example 6] Production of Solid-in-Oil-in-Water (S/O/W) by dispersing -60-201113049 of lg of lg produced in Production Example 5, dissolved in In 9 g of 0.1% polyoxyethylene hydrogenated castor oil 60 aqueous solution, S/0/W VC·PMg was produced. [Production Example 7] Production of CoQlO - Hydros Lozenges 1200 g of CoQlO - Hydros ' produced in Production Example 2 and 9 g of L-aspartate, 900 g of L-glutamic acid, and 900 g of L were produced. - arginine was mixed, and then 312 g of a tableting aid was added and sieved through a pulverizing granulator having a mesh size of 20. Further, 1560 g of crystalline cellulose '9672 g of Perfiller-102 was added and mixed, and then 156 g of sucrose monoester was added thereto for mixing and tableting to obtain a CoQlO-HydroS tablet. [Production Example 8] Production of VC·PMg — LipoS cream dose: 98 g of Plastibase, 32 g of sorbitan, 16 g of oxidized sand oil, and 20 g of squalane were stirred at a flow rate of 1 500 rPm using a static mixer. Heat to 90. (:, and completely dissolve it. After heating, the stirring speed is fixed at 1000 rpm, and cooled to 5 CTC. At this time, add 30 g of coconut oil which has dissolved l〇g of VC. PMg-LipoS, and then add 4S talc and 0.2 g of sodium metabisulfite was stirred at 2500 rpm for 1 minute. After cooling to 4 ° C, it was filled in an aluminum hose to obtain VC·PMg — LipoS cream (S/O). [Production Example 9] Manufacture of VC. PMg - LipoS oil Manufactured in VC of lg. PMg - LipoS' was added to 9 g of coconut oil, stirred and dissolved, and then dispensed into a special glass cosmetic bottle to make VC·PMg. -LipoS oil (S/O) -61 - 201113049 [Production Example 10] BCAA-LipoS gel was prepared by adding 64 g of pure water to a vessel, and then adding O.ig citric acid and stirring it to completely dissolve it. 10 g of sorbitan fatty acid ester and 16 g of BCAA-LipoS manufactured in Production Example 3 were charged, and stirred at 1500 rpm for 5 min, and further heated to 60 ° C. Further, 0.54 g of carrageenan, 0.18 g of tragacanth, and enamel were added. 〇9g of long bean gum is evenly dispersed in 9g of concentrated glycerin, and then put into the above solution, after the full amount of input, 'will stir The temperature was raised to 5000 rpm, and heated to a temperature of 85 ° C. After heating, the stirring speed was fixed at 3000 rPm, and then 9 g of propyl hydroxybenzoate was added, and heat sterilization was carried out for 30 minutes. The stirring speed was maintained at 3 000 rPm. And the temperature was lowered to 60 ° C to obtain BCAA-LipoS gel (S/W) » [Production Example 11] Manufacture of BCAA - LipoS oil in 16 g of BCAA-LipoS manufactured in Production Example 3, and 34 g of medium chain fatty acid was added. The triglyceride is stirred and dissolved, and then filled into a BCAA-LipoS oil (S/Ο) by a liquid and a binder filling machine. [Production Example 1 2] Production of a drug-surfactant complex (S) (Liquid-soluble of water-soluble drug, production example of LipoS) 18 g of sucrose fatty acid ester (ER-290) was completely dissolved in 75 g of hexane, and 2 g of VC. PMg was further added to 50 g of pure water. It is completely dissolved. This aqueous solution is added to the aforementioned hexane solution after dissolving sucrose fatty acid vinegar (ER--62-201113049 290), and emulsified by using a homogenizer at 2 〇〇 00 rPm' for 5 min. The hexane phase was removed by an evaporator. After removing the solvent, it was frozen at -45 °C. The lyophilization treatment was carried out, and the VC·PMg-surfactant complex (VC·PMg-LipoS) was prepared by completely removing the solvent. [Production Example 13] (Liquid-soluble of water-soluble drug, production example of LipoS oil) 3 g of medium chain fatty acid triglyceride was added to 90 g of sucrose fatty acid ester (ER-29), and the mixture was stirred until it was homogeneous. This solution was used as an interface active agent oil solution. Further, 1 〇g of L-cysteine was dissolved in 7 〇 g of pure water in another container, and the aqueous solution was added to the aforementioned surfactant oil solution. Emulsification was carried out using a homogenizer at 20,000 rpm for 5 min. After emulsification, lyophilization treatment was carried out at -45 °C, and the cysteine-surfactant complex (LipoS) (S/Ο) was prepared by completely removing water. [Production Example 14] (Hydrophilization of hydrophobic poorly soluble drug, production example of Hy d r 〇 S) 2 g of ubiquinone (CoQ10) was completely dissolved in 75 g of hexane. In addition, 18 g of SLS was added to 50 g of pure water and completely dissolved. This aqueous solution was added to the above-mentioned hexane solution in which CoQlO was dissolved, and emulsified at 20000 rpm for 5 minutes using a homogenizer. After emulsification, the hexane phase was removed by an evaporator. After the solvent was removed, it was freeze-dried at -45 °C, and the CoQlO-surfactant complex -63-201113049 (CoQlO - HydroS) was prepared by completely removing the solvent. [Production Example 15] (Liquid-soluble of water-soluble drug, Production Example of LipoS) 45 g of sucrose fatty acid ester (ER-290) was added to 300 g of hexane and completely dissolved. Further, 5 g of hydroxyproline (hereinafter referred to as HP) was further added to 30 g of pure water and completely dissolved. Further, this aqueous solution was added to the above-mentioned hexane solution in which sucrose fatty acid ester (ER-290) was dissolved, and emulsified at 20000 rpm for 5 minutes using a homogenizer. After emulsification, the hexane phase was removed by an evaporator. After removing the solvent, it was frozen at -45 °C and lyophilized, and the HP-surfactant complex (HP-LipoS) was prepared by completely removing the solvent. [Production Example 16] Production of Solid-in-Oil (S/0) 9.5 g of sesame oil was added to ·.5 g of VC·PMg-LipoS' obtained in Production Example 1, and S/deuteration was obtained by dissolution. VC·PMg. [Production Example 17] Production of Solid-in-Oil (S/O) 9.5 g of sesame oil was added to HP.5 g of HP-LipoS' obtained in Production Example 15, and S/Oized HP was obtained by dissolution. . [Manufacturing Example 18] Production of Solid-in-Oil (S/O) was 0.5 g of VC·PMg-LipoS obtained in Production Example 1, and 0.5 g of HP-LipoS' obtained in Production Example 15 was added to 9 g. Sesame oil, -64- 201113049 A mixture of VC·PMg and S/Oized HP obtained by dissolving is dissolved [Example 1] (Resistance by drug of s/ο) The s/o VC · PMg produced in Example 5 was examined for long-term stability during two years at room temperature. The positive control used a VC.PMg solution which was not subjected to S/O, and the negative control used a dispersion medium used for S/deuteration. The photograph of Fig. 6 was preserved at room temperature for 2 years. The latter's from the left end of the picture were S/Ο VC. PMg, the VC·PMg solution of the positive control, and the S/Ο of the negative control (〇). . The VC·PMg solution showed a browning change over time, whereas the S/0 VC·PMg did not brown at all in the same state as the dispersing medium, indicating extremely stable. [Example 2] (Skin absorption of drug by S/Ο) The increase in skin absorbability was examined using S/deuterated VC·PMg' manufactured in Production Example 5. The positive control was adjusted to adjust the vitamin C content to the same amount of 1 〇mg /mL ascorbyl palmitate trisodium phosphate (vitamin C derivative, hereinafter referred to as APPS) aqueous solution, and the negative control was adjusted without S/Ο. The same amount of an aqueous solution containing only VC·PM g. The abdomen of the mice in which the ether was intoxicated with these samples was coated with 50 #L per cm 2 . After 4 hours, the skin tissue of the coated portion was peeled off, and after weighing, the content of Vital-65-201113049 C was quantified using a hydrazine colorimetric method. In Fig. 7, the vertical axis indicates the content of vitamin C (/zg) relative to the weight g of the mouse skin tissue. The horizontal axis is the S/deuterated VC · PMg coating group and the VC · PMg coating group from the front left end. (negative control group), and APPS coating group (positive control group). Compared with the group of VC·PMg only, the content of vitamin C in the skin of the S/deuterated VC·PMg group increased significantly. In addition, it is the same or increased compared with the APPS of the vitamin C derivative. By S / 0, the skin absorption of vitamin C can be significantly improved. In addition, the stability of APPS is not good, and the S/O VC · PMg with excellent stability is clearly superior. [Example 3] (Blocking of bitterness and astringency of the trophic factor of the drug-surfactant complex) Using the branched amino acid produced in Production Example 1 to carry out a functional experiment of 8 normal testers. The functional experiments were carried out using 1) s-branched amino acid, and 2) an equal amount of a mixture of branched-chain amino acids and a surfactant. Here, in order to avoid the influence of the characteristic odor of the branched amino acid and the additive on the taste judgment, the lemon oil of 重量·〇% by weight is added to the samples. The functional test was carried out in such a manner that the regularity of the sample number could not be inferred, and after random numbering, the subjects were weighed to a sample of 5 g and given a position. The official can perform the experiment twice, and the results are shown in Table 1. According to the results, it is possible to remarkably improve the unpleasant mouthfeel such as bitterness and astringency caused by S-forming. -66- 201113049 Table 1 Bitter taste ABCDEFG Η 1 wave 1 time te yi w Weakness Μ jw\ Weak Αητ IIU* /»Ν\ ίΕ Weak 2 wave 1 strong strong and strong 1 strong 2 wave no weak Weak weak Ατττ. im: Μ j \ \\ Weak 2) 2nd strong, strong, strong and strong [Example 4] (Dose-soluble of water-soluble drugs and one dose of hydrophobic drugs) 5 g of VC·PMg-surfactant complex (VC · PMg - LipoS ) prepared in Preparation Example 12 and 〇. 5 g of vitamin E (VE) were added to lkg olive oil, and dispersed by using a stirrer to obtain a clear and uniform The solution. The rotary soft capsule was used to form a sputum filling machine, and the uniform solution was separately filled and formed in a predetermined amount of 4 g to prepare a high-content uniform soft capsule containing VC·PMg and VE. The shape of the soft capsule can be manufactured in a twisted shape in addition to the general long oval shape. A soft capsule of the same form is used to form a sputum filling machine, and 0.1 g of the quantitative form is separately filled and formed into a high-content uniform soft capsule containing VC • PMg and VE. On the contrary, 〇.5gVC.PMg and 〇.5gVE were directly dispersed in lkg olive oil containing 4.5g of sucrose fatty acid ester (ER-290), and no clarification was observed. VC·PMg was also observed in the liquid. The suspended state assumes a floating state. When it is left to stand, a precipitate is observed, and it is impossible to form a soft capsule. The soft capsule after the preparation can be packaged by the easy-to-tear bubble package formed by the plastic film and the aluminum film, so that the soft capsule can be easily taken out even if the hardness is soft, and can be made clean and easy to carry and carry. product. Soft capsules can also be packaged in extruded bubble packs. Thus, the VE of the hydrophobic poorly soluble trophic factor can be uniformly dispersed by performing -67-201113049 VC · PMg - surfactant complex (VC . PMg - LipoS ) on the VC . PMg of the water-soluble trophic factor. Dissolved in vegetable oil. [Example 5] (Example of S/W in which CoQlO-Hydrates was finely dispersed and dissolved in an aqueous solution of a drug-containing electrode for iontophoresis) Dissolved in a 0.3% citric acid buffer solution (PH6).
Carboxyvinylpolymer ( B.F. Goodrich公司製，Carboxyvinylpolymer 940)。以氫氧化鈉將該溶液調整爲pH6，以全量爲5〇g ’ 得 0·4 % Carboxyvinylpolymer 溶液（以下稱作 〇·4% Carboxyvinylpolymer水溶液）。將製造例14所調製之5g之 CoQlO—界面活性劑複合體（CoQlO— Hydros)，使用攪 拌子進行分散於0.4% Carboxyvinylpolymer水溶液50g可得 —澄清均勻之溶解液（以下稱作含CoQlO- HydroS之0.4% Carboxyvinylpolymer水溶液）。使用離子電滲裝置，碳電 極連接電氣刺激裝置之陽極，氯化銀電極則連結電氣刺激 裝置之陰極。陽極側之液體槽放置2ml之0.4% Carboxyvinylpolymer水溶液，陰極側之液體槽放置2ml之 含 CoQlO — HydroS 之 0.4% Carboxyvinylpolymer水溶液，以 0.2mA電流進行通電30分鐘。 反之，直接將〇.5g CoQlO，分散於含4.5gSLS之50g之 0.4% Carboxyvinylpolymer水溶液，不會形成澄清，亦觀 察到CoQ 1 0於液體中以懸濁狀態呈現浮游狀態。而將其靜 -68- 201113049 置時會觀察到沉澱物，無法調製爲離子電滲用含營養因子 之電極凝膠水溶液。如此，藉由對難溶性營養因子之 CoQlO ’進行CoQlO -界面活性劑複合體（c〇Ql〇 -Hydros )化’可調製均句地分散、溶解於離子電滲用含營 養因子之電極凝膠水溶液。 [實施例6] (藉由半胱胺酸一LipoS油劑化之掩蔽） 針對製造例13所調製之半胱胺酸-LipoS油之臭味， 實施正常試驗者8名之官能實驗。其結果，獲得8名均感覺 到半胱胺酸特殊的臭味被減低之結果。 [實施例7] (藉由S/Ο化HP與S/Ο化VC · PMg之經皮投藥之膠原蛋白 量增加） 將27隻體重爲250g之雄性SD小鼠如下所示分爲5群， 實施經皮投藥試驗。亦即，將1)使VC· PMg成爲濃度1% 及使HP成爲濃度1%分散於芝麻油中之溶液，作爲對照群 。2 )將製造例16所製造之含1%VC · PMg之S/Ο化VC · PMg液，作爲實驗群。3 )製造例17所製造之含l%S/0化HP 之HP液。4 )製造例18所製造之l%S/0化VC · PMg+l%S/0 化HP之4群，分別使用6隻。進而5)於芝麻油投藥群中各 使用3隻，作爲陰性對照群，而實施試驗。 將醚麻醉下之小鼠的背部剃毛，於以剪刀剪開深至背 -69- 201113049 部皮膚肌肉層之5cm長傷口之上，將切開部位以Vistat®( skin staplers )閉合，而製作出皮膚創傷，於創傷面上塗 佈100 V丨檢體每日一次，連續進行塗佈17天。 塗佈後，第7天及第1 7天小鼠背部皮膚組織中膠原蛋 白濃度之測定結果示於表2與圖8。另外，以芝麻油進行塗 佈後第17天皮膚組織中之膠原蛋白濃度爲1〇〇%時，將各群 所算出之膠原蛋白濃度之結果示於表3及圖9。 表2 群 第7天 第17天 一 膠原蛋白濃度 (n=3) 土 S.D· 膠原蛋白濃度 (n=3) 土S.D. 芝麻油 0.51 0.04 _ l%vc溶液 1%HP溶液 0.42 0.04 0.49 0.07 i%vc-s/o 0.43 0.05 0.51 0.04 l%HP-S/0 0.40 0.04 0.50 0.02 _ l%VC-S/0 l%HP-S/0 0.42 0.04 0.55 0.06 表3 第Π天 群 膠原蛋白濃度 (η=3) 芝麻油 100% 1%VC溶液 1%HP溶液 96% l%VC-S/0 101% l%HP-S/0 98% l%VC-S/0 109% l%HP-S/0 -70- 201113049 於對照群之投藥1%VC · PMg+l%HP之皮膚組織中之膠 原蛋白濃度並未增加，但於實驗群4)之l%S/0化VC · PMg+l%S/0化HP之經皮投藥群中，明顯發現增加。該增 加於實驗群2 )之僅經皮投藥S/O化VC · PMg之群，或實驗 群3 )之僅經皮投藥S/Ο化HP均未發現，由此可明確得知， 藉由將VC · PMg與HP進行S/Ο化，以一劑型之方式同時經 皮投藥可增加。 [製造例19]製造疏水性難溶性藥物/親水性胺基酸水溶液 於純水1L中，溶入10g檸檬酸及80g乳糖醇之水溶液， 再加入120g之L-天門冬胺酸鈉、120g之L-麩醯胺酸、120g 之L-精胺酸並使其完全溶解。之後於前述水溶液中加入製 造例2所調製160g之CoQlO-hydroS並使其溶解，製造 CoQ 10/親水性胺基酸配合水溶液。 [製造例20]製造疏水性難溶性胺基酸/乳糖醇凝膠 將製造例3所調製之16gBCAA/ LipoS，均勻分散於 144g之0.1%聚氧乙烯氫化蓖麻油60水溶液中之後，加熱至 85°C同時，以高速均質機進行攪拌（20,000rpm )，製作 LipoS /W乳糜液。將該乳糜液以-45 °C進行冷凍後，以 真空冷凍乾燥機進行脫水，製成親水性BCAA/ Lipo/ hydros (以下稱作 BCAA/ / )。 另外將2.8g之乳糖醇·一水合物（Danisukosuitonazu ，USA)，加入25.2g之純水中，以l，5 00rpm攪拌並使其溶 -71 - 201113049 解，進而加入I60g之BCAA/ /，充分溶解之後，再加入 11.28g之卡拉膠、5.64g之黃耆膠、0.0188g之長豆角膠、 2.3 4 g之濃甘油，並使其均句地分散後，加熱至8 5 °C。加 熱後將攪拌速度提高至3,0 0〇rpm，接著投入lg之羥基苯甲 酸丙酯，進行30分鐘殺菌後，進行塡充、放熱，調製成 BCAA/乳糖醇凝膠。 [製造例21]製造配合皮膚營養因子之乳霜劑 將9.7g之Eagle's MEM培養基粉末（商品名：DAIGO )溶解於40ml純水中。另外再使40g之蔗糖脂肪酸酯（ER-290)完全溶解於380g之己烷後’加入該MEM水溶液’以 均質機20,000rpm，進行乳化5分鐘。進行乳化後再以蒸發 機去除己烷相。隨即以_45°c冷凍並進行冷凍乾燥處理， 可調製MEM-界面活性劑複合體（MEM— LipoS)。 量取98g之Plastibase、32g之山斎醇、16g之二氧化石夕 油、20g之角鯊烷’使用攪拌機加熱至90 °C同時以1,5〇〇 rpm進行攪拌，並使其完全溶解。加熱後將攪拌速度降爲 l，000rpm，並冷卻至50°C 。此時加入已添加使濃度爲 0.05%之維他命£之3(^之椰子油’再加入1〇8之1^^1〜 LipoS，進而加入4g之滑石及〇.2g之焦亞硫酸鈉’以 2,500rpm攪拌10分鐘。冷卻至40°C後’充塡於銘製軟管中 ，得MEM — LipoS/VE皮膚營養乳霜。 [實施例8]對眼黏膜剌激之配合效果 -72- 201113049 於經添加〇 · 〇 5 %維他命E (以下稱作V E )之純化橄檀 油中，以使VC含量成爲0.05%而添加製造例1所製造之VC /PMg— LipoS，製作 VC/PMg/LipoS-VE。反之作爲對 照者係分別添加與VC/ PMg及VE均爲相同含量之生理食 鹽水或純化橄欖油之物理性混合物，提供於實驗作爲對照 〇 試驗係使用體重2.0kg左右之2隻雄兔（紐西蘭大白兔 種），分別使用〇.2ml對其眼部進行點藥，於30分鐘後、1 小時後、2小時後觀察對眼黏膜的刺激狀態。試驗係包含 安排有1星期之休藥期，以交叉試驗，將未用於試驗的另 一側眼睛作爲陰性對照，以下述之眼黏膜刺激狀態評價基 準，以目視判定對眼黏膜之刺激狀態。試驗結果示於表4 。另外，試驗1之眼黏膜刺激試驗之第1小時兔子眼部周圍 照片示於圖1 0。 <眼黏膜刺激狀態評價基準> (評價） （內容） 陰性（-) :眼黏膜未發生發炎症狀。 僞陽性（±) :眼黏膜發生微弱的發炎症狀。 陽性（+) :眼黏膜發生發炎症狀。 -73- 201113049 表4 試驗 投用藥 受藥後時 :間(小時） 投藥前 0.5 1.0 2.0 試驗1 對照群 VC/PMg+VE — + + + 試驗群 VC/PMg- LipoS +VE — — — 一 試驗2 對照群 VC/PMg+VE — + + + 試驗群 VC/PMg_ LipoS +VE — — 一 — 於滴入將VC/ PMg及VE混合後之對照群物理性的混 合物（對照群）之眼，可以明顯發現發炎刺激（白色箭頭 所指處）。反之在溶解、配合VC/PMg-LipoS之試驗群 中，於滴下後至2小時之觀察時間內，完全未發現黏膜刺 激。由上述結果明確可知本配合劑可避免對黏膜的刺激性 [實施例9]藉由使疏水性難溶性藥物CoQ 10之Hydro S化於 水溶液中安定性 使l〇g之泛醌（以下稱作CoQlO)完全溶解於3 75g之己 烷中。另外於250g之純水中加入90g聚氧乙烯氫化蓖麻油 60 (以下稱作HC-60 )並使其均勻分散且完全溶解。將該 水溶液加入已溶解CoQlO之己烷溶液中，使用均質機以 2 0,0 00rpm，進行乳化5分鐘。進行乳化後再以蒸發機去除 己烷相後，以-45 °C冷凍進行冷凍乾燥處理，藉由完全去 除溶媒，可調製成CoQlO—界面活性劑複合體（CoQlO-HydroS )。將此處所得之CoQlO — hydros，調製成爲 CoQ 10含量爲〇.1 %及1 %水溶液作爲試驗群。反之對照群則 -74- 201113049 爲於250g之純水中加入90g之HC-60，使其均勻分散且完全 溶解，分別調整CoQlO含量爲1%及0.1%後’準備均質機以 20,000rpm，進行乳化5分鐘後者。將試驗群及對照群之 CoQ 10含量爲0.1 %及1 %之溶液裝入試管中’靜置於室溫。 於各水溶液之剛靜置時、1天後、2天後之安定性以目視觀 察。靜置2天後各水溶液之狀態照片示於圖1 1 ° 對照群均於放置1天後發現CoQlO之沉降，與〇」％濃 度相比，1%者更爲顯著。照片爲靜置於室溫下2天者’與 第1天相比，對照群0.1%或1 %濃度者CoQlO之沉降更爲顯 著。照片中箭頭所指者爲CoQ 10之沉降物。反之在試驗群 (CoQlO - hydro經S化後者），均未發現沉降，於水溶液 中極爲安定。 [產業上的可利用性] 本發明译藉由製作將不僅醫藥品，亦使用於食品及化 妝品之藥物內包於界面活性劑之藥物-界面活性劑複合體 Solid ( S )，及其分散液之 Solid-in-Water ( S/W )、 Solid-in-Oil ( S/Ο)以及 Solid-in-Oil-in-Water ( S/0/W) ，使任意改變藥物的物性變爲可能，其結果，由可將水溶 性藥物與難溶性藥物分散，溶解於同一種液體中開始，計 畫安定性，提高對生物體的吸收，掩蔽苦味及苦澀味，不 僅製成軟膠囊劑及經口凝膠劑，亦變成爲可應用於油性注 射劑及經皮劑，錠劑及硬膠囊劑等各式各樣的製品。 另外藉由本方法使難溶性藥物水溶性化，而可使其與 -75- 201113049 水溶性藥物均勻地分散、溶解於水中。該液體亦可製劑化 爲經口凝膠劑，注射劑及經皮劑，錠劑及硬膠囊劑。 特別係將難溶性藥物以親水性界面活性劑被覆後之 Hydros，由於可均勻地分散、溶解於離子電滲法用電極水 溶液（S / W )，而可計劃藉由離子電滲法之經皮吸收。亦 可應用於同樣的爲促進經皮吸收之方法之離子導入法’及 以超音波促進經皮吸收方法之超音波電滲法’電氣導入法 之電穿孔法用之營養因子溶解液方面。 【圖式簡單說明】 [圖1]表示藥物-界面活性劑複合體製造方法之圖。 [圖2]藥物一界面活性劑複合體Solid (S)之模式圖。 [圖 3]Solid-in-Water(S/W)之模式圖。 [圖 4]Solid-in-Oil ( S/O)之模式圖。 [圖 5]Solid-in-Oil-in-Water(S/0/W)之模式圖。 [圖6]顯示因S/0化VC · PMg安定化之照片。 [圖7]顯示因S/0化而提高維他命C皮膚吸收性圖。 [圖8]顯示塗佈VC · PMg與HP後，小鼠背部皮膚組織 中之膠原蛋白濃度的經時變化圖。 [圖9]顯示藉由組合複數種S/0化之藥物於第17天膠原 蛋白量上升之圖。 [圖1 〇]眼黏膜刺激試驗第1小時白兔之眼部周圍之照片 (試驗1 )。 [圖1 1]顯示CoQ 10於水溶液中安定性（第2天）之照片。 -76-Carboxyvinylpolymer (manufactured by B.F. Goodrich, Carboxyvinylpolymer 940). This solution was adjusted to pH 6 with sodium hydroxide, and a total amount of 5 〇g ' was obtained as a 0.4% Carboxyvinylpolymer solution (hereinafter referred to as 〇·4% Carboxyvinylpolymer aqueous solution). 5 g of the CoQlO-surfactant complex (CoQ10-Hydrates) prepared in Preparation Example 14 was dispersed in a 0.4% aqueous solution of Carboxyvinylpolymer using a stirrer to obtain a clear and uniform solution (hereinafter referred to as CoQlO-HydrS-containing solution). 0.4% Carboxyvinylpolymer in water). Using an iontophoresis device, the carbon electrode is connected to the anode of the electrical stimulation device and the silver chloride electrode is connected to the cathode of the electrical stimulation device. 2 ml of a 0.4% aqueous solution of Carboxyvinylpolymer was placed in the liquid tank on the anode side, and 2 ml of a 0.4% Carboxyvinylpolymer aqueous solution containing CoQlO - HydroS was placed in the liquid tank on the cathode side, and electricity was supplied at a current of 0.2 mA for 30 minutes. On the contrary, 〇.5g of CoQlO was directly dispersed in a 0.4% aqueous solution of 0.4% Carboxyvinylpolymer containing 4.5 g of SLS, and no clarification was observed. It was also observed that CoQ10 exhibited a floating state in a suspended state in the liquid. However, when it was static -68-201113049, precipitates were observed, and it was not possible to prepare an aqueous solution of an electrode gel containing trophic factors for iontophoresis. Thus, the CoQlO-surfactant complex (c〇Ql〇-Hydros) can be prepared by coQlO' of the poorly soluble trophic factor, and can be uniformly dispersed and dissolved in the electrode gel containing trophic factor for iontophoresis. Aqueous solution. [Example 6] (masking by cysteine-LipoS oiling) The odor of the cysteine-LipoS oil prepared in Production Example 13 was subjected to a functional experiment of 8 persons in a normal test. As a result, it was found that all of the eight people felt that the special odor of cysteine was reduced. [Example 7] (Increased amount of collagen by transdermal administration of S/deuterated HP and S/deuterated VC·PMg) 27 male SD mice weighing 250 g were divided into 5 groups as follows. A transdermal drug test was performed. That is, 1) a solution in which VC·PMg was made to have a concentration of 1% and HP was dispersed in sesame oil at a concentration of 1% was used as a control group. 2) The S/deuterated VC·PMg liquid containing 1% VC·PMg produced in Production Example 16 was used as an experimental group. 3) The HP liquid containing 1% S/0 HP produced in Production Example 17. 4) Four groups of 1% S/0 VC, PMg + 1% S/0 HP manufactured in Production Example 18 were used, and 6 were used. Further, 5) 3 animals were used in each of the sesame oil administration groups, and a test was carried out as a negative control group. The back of the mice under ether anesthesia was shaved, and the cuts were closed with Vistat® (skin staplers) by cutting the deep-to-back-69-201113049 skin muscle layer with a 5 cm long wound. For skin wounds, a 100 V test specimen was applied to the wound surface once a day for 17 days. The results of measurement of collagen concentration in the skin tissue of the back of the mice on the 7th day and the 17th day after the application were shown in Table 2 and Figure 8. Further, when the collagen concentration in the skin tissue on the 17th day after the sesame oil coating was 1%, the results of the collagen concentrations calculated for each group are shown in Table 3 and Fig. 9. Table 2 Group 7 Day 17 Day 17 Collagen Concentration (n=3) Soil SD· Collagen Concentration (n=3) Soil SD Sesame Oil 0.51 0.04 _ l%vc Solution 1% HP Solution 0.42 0.04 0.49 0.07 i%vc -s/o 0.43 0.05 0.51 0.04 l%HP-S/0 0.40 0.04 0.50 0.02 _ l%VC-S/0 l%HP-S/0 0.42 0.04 0.55 0.06 Table 3 Dianthus group collagen concentration (η= 3) Sesame oil 100% 1% VC solution 1% HP solution 96% l%VC-S/0 101% l%HP-S/0 98% l%VC-S/0 109% l%HP-S/0 - 70- 201113049 The concentration of collagen in the skin tissue of the control group of 1% VC · PMg + 1% HP did not increase, but in the experimental group 4) l% S / 0 VC · PMg + l% S / In the transdermal drug-administered group of HP, it was found to increase. The increase in the transdermal administration of S/O VC·PMg in the experimental group 2) or the transdermal administration of S/deuterated HP in the experimental group 3) was not found, thereby being clearly known by The S/cyanization of VC·PMg with HP can be increased by simultaneous transdermal administration in a single dosage form. [Production Example 19] A hydrophobic poorly soluble drug/hydrophilic amino acid aqueous solution was prepared in 1 L of pure water, and an aqueous solution of 10 g of citric acid and 80 g of lactitol was dissolved, and 120 g of sodium L-aspartate and 120 g of the solution were added. L-glutamic acid, 120 g of L-arginine and completely dissolved. Then, 160 g of CoQlO-hydroS prepared in Preparation Example 2 was added to the aqueous solution and dissolved to prepare a CoQ 10 / hydrophilic amino acid complex aqueous solution. [Production Example 20] Production of a hydrophobic poorly soluble amino acid/lactitol gel 16 g of BCAA/LipoS prepared in Production Example 3 was uniformly dispersed in 144 g of a 0.1% polyoxyethylene hydrogenated castor oil 60 aqueous solution, and then heated to 85. At the same time, a high-speed homogenizer was used for stirring (20,000 rpm) to prepare a LipoS /W emulsion. The chyle solution was frozen at -45 °C, and then dehydrated by a vacuum freeze dryer to obtain hydrophilic BCAA/Lipo/hydros (hereinafter referred to as BCAA/ / ). Separately, 2.8 g of lactitol·monohydrate (Danisukosuitonazu, USA) was added to 25.2 g of pure water, stirred at 1,500 rpm and dissolved -71 - 201113049, and then I60 g of BCAA / / was added. After dissolution, 11.28 g of carrageenan, 5.64 g of tragacanth, 0.0188 g of long bean gum, and 2.3 g of concentrated glycerin were added and uniformly dispersed, and then heated to 85 ° C. After heating, the stirring speed was increased to 3,000 rpm, and then lg of propyl hydroxybenzoate was added thereto, and after sterilization for 30 minutes, charging and exotherm were carried out to prepare a BCAA/lactose gel. [Production Example 21] Production of a cream for skin trophic factor 9.7 g of Eagle's MEM medium powder (trade name: DAIGO) was dissolved in 40 ml of pure water. Further, 40 g of sucrose fatty acid ester (ER-290) was completely dissolved in 380 g of hexane, and then the MEM solution was added to the MEM solution at 20,000 rpm for 5 minutes. After emulsification, the hexane phase was removed by an evaporator. The MEM-surfactant complex (MEM-LipoS) was prepared by freezing at _45 °c and lyophilizing. 98 g of Plastibase, 32 g of behenyl alcohol, 16 g of cerium oxide oil, and 20 g of squalane were heated to 90 ° C using a stirrer while stirring at 1,5 rpm, and completely dissolved. After heating, the stirring speed was lowered to 1,000 rpm and cooled to 50 °C. At this time, add 3 (2 of the coconut oil of the concentration of 0.05% of the vitamin oil added to 1 〇 8 of 1 ^ ^ 1 ~ LipoS, and then add 4 g of talc and 〇. 2g of sodium metabisulfite ' to 2,500 rpm Stir for 10 minutes. After cooling to 40 ° C, 'filled in the original hose, MEM - LipoS / VE skin nutrition cream. [Example 8] The effect of eye mucous membrane stimulation -72- 201113049 VC/PMg/LipoS-VE was prepared by adding VC/PMg-LipoS manufactured in Production Example 1 to a purified olive oil of 〇·〇5 % of vitamin E (hereinafter referred to as VE) so as to have a VC content of 0.05%. On the contrary, as a control, a physical mixture of physiological saline or purified olive oil having the same content as VC/PMg and VE was separately added, and the experiment was used as a control 〇 test system using two male rabbits weighing about 2.0 kg ( New Zealand white rabbits were treated with 〇.2ml, and the eye mucosa was observed after 30 minutes, 1 hour, and 2 hours. The test included a one-week break. During the drug phase, the other side of the eye that was not used for the test was used as a negative pair in a crossover test. According to the following evaluation criteria of the eye mucosal irritation state, the irritation state of the eye mucosa was visually determined. The test results are shown in Table 4. In addition, the photo of the rabbit eye around the first hour of the eye mucosa stimulation test of Test 1 is shown in Fig. 1. 0. <Evaluation of eye mucosal irritation state> (Evaluation) (Content) Negative (-): No symptoms of inflammation occurred in the mucous membrane of the eye. False positive (±): A weak inflammation of the eye mucosa. Positive (+): Eye Inflammation of the mucous membrane. -73- 201113049 Table 4 Test after administration of the drug: between (hours) before administration 0.5 1.0 2.0 Test 1 Control group VC / PMg + VE - + + + test group VC / PMg - LipoS + VE — — — One test 2 Control group VC/PMg+VE — + + + Test group VC/PMg_ LipoS +VE — — I — Physical mixture of control group after instillation of VC/PMg and VE (control group) In the eye of the eye, the irritating stimulus can be clearly found (pointed by the white arrow). Conversely, in the test group dissolved and matched with VC/PMg-LipoS, no mucosal irritation was found at any observation time after the dropping to 2 hours. The above results clearly show that this The compounding agent can avoid irritating to the mucosa [Example 9] The ubiquinone of the 〇g (hereinafter referred to as CoQlO) is completely dissolved in 3 by the Hydro S of the hydrophobic poorly soluble drug CoQ 10 in the aqueous solution. In 75 g of hexane, 90 g of polyoxyethylene hydrogenated castor oil 60 (hereinafter referred to as HC-60) was added to 250 g of pure water and uniformly dispersed and completely dissolved. This aqueous solution was added to a hexane solution in which CoQlO was dissolved, and emulsified for 5 minutes at 20 00 rpm using a homogenizer. After emulsification, the hexane phase was removed by an evaporator, and then freeze-dried at -45 °C to form a CoQlO-surfactant complex (CoQlO-HydroS) by completely removing the solvent. The CoQlO-hydros obtained here was prepared into a test group having a CoQ 10 content of 0.1% and 1% aqueous solution. On the contrary, the control group is -74-201113049. To add 90g of HC-60 to 250g of pure water, it is uniformly dispersed and completely dissolved. After adjusting the CoQlO content to 1% and 0.1%, respectively, the preparation homogenizer is performed at 20,000 rpm. Emulsify the latter for 5 minutes. A solution of the test group and the control group having a CoQ 10 content of 0.1% and 1% was placed in a test tube and allowed to stand at room temperature. The stability of each aqueous solution immediately after standing, one day later, and two days later was visually observed. A photograph of the state of each aqueous solution after standing for 2 days is shown in Fig. 1 1 ° The control group was found to have settled CoQlO after being placed for 1 day, and 1% was more remarkable than the 〇"% concentration. The photograph was taken at room temperature for 2 days. The sedimentation of CoQlO was more pronounced in the control group at a concentration of 0.1% or 1% compared with the first day. The arrow in the photo refers to the sediment of CoQ 10. On the contrary, in the test group (CoQlO-hydro via S-the latter), no sedimentation was found and it was extremely stable in the aqueous solution. [Industrial Applicability] The present invention is a drug-surfactant complex Solid (S) which is prepared by coating a drug which not only a pharmaceutical product but also a food and a cosmetic with a surfactant, and a dispersion thereof Solid-in-Water (S/W), Solid-in-Oil (S/Ο), and Solid-in-Oil-in-Water (S/0/W) make it possible to change the physical properties of the drug. As a result, the water-soluble drug and the poorly soluble drug can be dispersed and dissolved in the same liquid, and the stability can be planned, the absorption of the living body can be improved, the bitterness and bitterness can be masked, and not only a soft capsule and a mouth can be made. The gelling agent also becomes a variety of products which can be applied to oily injections, transdermal agents, lozenges and hard capsules. Further, by the method, the poorly soluble drug is made water-soluble, and it can be uniformly dispersed and dissolved in water with the -75-201113049 water-soluble drug. The liquid can also be formulated into oral gels, injections and transdermal agents, troches and hard capsules. In particular, Hydros, which is coated with a poorly soluble drug with a hydrophilic surfactant, can be uniformly dispersed and dissolved in an aqueous electrode solution (S / W) for iontophoresis, and can be planned by iontophoresis. absorb. It can also be applied to the same ionic nutrient solution for electroporation by the iontophoresis method for promoting percutaneous absorption and the ultrasonic permeation method for electroporation by the ultrasonic percutaneous absorption method. BRIEF DESCRIPTION OF THE DRAWINGS [Fig. 1] A view showing a method of producing a drug-surfactant complex. [Fig. 2] A schematic diagram of a drug-surfactant complex Solid (S). [Fig. 3] A pattern diagram of Solid-in-Water (S/W). [Fig. 4] A pattern diagram of Solid-in-Oil (S/O). [Fig. 5] A pattern diagram of Solid-in-Oil-in-Water (S/0/W). [Fig. 6] A photograph showing the stabilization of VC/PMg due to S/0. [Fig. 7] shows an increase in the absorption profile of vitamin C skin due to S/0. Fig. 8 is a graph showing temporal changes in collagen concentration in the skin tissue of the back of mice after application of VC·PMg and HP. Fig. 9 is a graph showing the increase in the amount of collagen on the 17th day by combining a plurality of S/0 drugs. [Fig. 1 〇] Photograph of the eye around the white rabbit on the 1st hour of the mucous membrane irritation test (Test 1). [Fig. 1 1] A photograph showing the stability (Coase 2) of CoQ 10 in an aqueous solution. -76-