200815052 七、指定代表圖： ()本案指定代表圖為··第（一）圖。 (一）本代表圖之元件符號簡單說明： ^:本案若有化學式時，請揭示最能顯示發明特徵的化學 式. 無 φ 九、發明說明： 【發明所屬之技術領域】 本發明係揭露一種控制劑型與其製備方法。 • 【先前技術】 - 藉由緩釋（如stained release)或控制藥物釋放((：〇11仕〇116(1 release)的藥物傳輸系統可有效減少病人服用藥物之次數，進而 提升病人服藥的配合度。許多不同的方法都被應用於生產緩釋或 鲁控制釋放的藥物傳輸系統。這些方法包括，例如以高分子聚合物 塗層（coatmg)於錠劑或圓粒上，或以不溶或難溶之聚合物生產錠 劑。 舉例而言，其中錠劑和圓粒塗層的製造是相當費時的，並且 通常是❹水溶性㈣幅職。-般而言，這類的錠劑和圓粒不 5 200815052 適合用來製備對溼氣敏感的藥物。同樣地，若僅僅是使用不溶或 難溶之聚合物，也會因批次不同的聚合物品質影響錠劑的製備， 而無法有效表現藥效的再現性（美國專利申請公開號 20060099254)。 美國第 5, 055, 306號專利（U.S. Pat. No. 5, 055, 306)揭示一 緩釋劑型配方（a sustained-release formulation)，此配方具200815052 VII. Designation of representative representatives: () The representative representative of this case is the picture of (1). (1) A brief description of the symbol of the representative figure: ^: If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention. No φ IX. Description of the invention: [Technical field of invention] The present invention discloses a control Formulation and preparation method thereof. • [Prior Art] - By slow release (such as stained release) or controlled drug release ((: 〇11仕〇116 (1 release) drug delivery system can effectively reduce the number of times patients take drugs, thereby improving the patient's medication Many different methods have been applied to the production of sustained release or controlled release drug delivery systems, including, for example, high molecular weight polymer coatings (coatmg) on tablets or pellets, or insoluble or difficult. Soluble polymers produce tablets. For example, the manufacture of tablets and pellets is quite time consuming and is usually water soluble (four). In general, such tablets and pellets Not 5 200815052 It is suitable for the preparation of drugs sensitive to moisture. Similarly, if only insoluble or poorly soluble polymers are used, the preparation of tablets will be affected by the quality of different batches of polymers, and the drug cannot be effectively expressed. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Equipment
有一顆粒核心包含藥物活性成分，與一大幅覆蓋整個核心表面之 塗層，其中塗層含有以丙烯酸乙酯（ethyl acrylate)與甲基丙烯 酸甲酯（methyl methacrylate)，和一種水溶性羥基纖維素衍生物 (hydroxylated cellulose derivative)等組成之天然共聚合物 (copolymer)，此為一不溶於水，但遇水會膨脹之薄層。美國第 4, 952, 402號專利（U.S· Pat· Να 4, 952, 402)揭示一控制釋放粉 末(a controlled release powder)，包含成分有一活性物質與下 列至少一種物質之緊密混合：無毒且不具水溶性，具通透性，不 可通透性，生物可分解之控讎«合物，或這些物^混合物。 大部份控制釋放成分或劑型是由兩部分組成，即核心和塗 層。核心含活性成分和賦形劑（excipients)。塗層材料在其成 刀、組成比例、溶解度、疏水或親水性而有許多變化。不同的配 方和製程參數可以有«多樣的組合，以達賴物釋放最佳化的 形式（如塗料的層數、與添加塑化劑的種類和數量）。活性成分從 核心釋放出來的型態正逐漸被探討，將不溶於水的液態懸浮物， 6 200815052 與腸溶聚合物(enteric polymer)混合以用於錠劑的塗層也在研究 中，例如乙基纖維素(ethyl cellulose):羥丙基甲基纖維素琥站 酸酯（hydroxypropyl methycellulose acetate succinate) (EC ·· HPMCAS)和乙基纖維素：甲基丙稀酸乙酯共聚物 ethyl acrylate copolymer) (EC ： Eudragit L) (F. Siepmann et 5/，2005，/· 你/從见1〇5: 226-239)。 關於控釋製劑的主要問題之一在於服藥後的第一個小時内釋 .放了大量的活性成分，通常這樣的釋放結果將導致藥物濃度在血 液中濃度突然的上昇。這樣的情形，在許多情況下會使得人體無 籲法接受而產生毒性問題。另一方面，因為在給藥後突然且快速的 釋放大量活性物質，也同時降低了活性藥物成分的停留時間。 第一個問遞在於，當使用微膠囊（micr〇encapsUiati〇n)的常 規包覆技術時常得到相對低效包封率(encapsulation rate)，特 別是當活性成分是一種水溶性藥用產品。 - 第三侧題必須解決的是在於發展這些配辦會產生活性成 分不穩定的問題，因為活性成分在生產微粒(mic卿here)時需要 面對嚴苛的條件’例如高溫或在溶縫發步驟中會和有機溶劑有 長時間的接觸。 為解決上述種種問題，已有許多試驗展開研究。因此一些添 ft像是糖、油腊、壤、蛋白質、聚合物、鹽類或酸都已用於 她劑喊__ml_phere)巾，料_丨，是作為將 200815052 藥用產品保留在微粒中的物質，可以增加微膠囊包覆技術的效 率，甚至可能的話，可以保護活性成分，在包封的過程中，扮演 穩定劑的角色。 • 然而，在微粒中加入這些添加物，會導致活性成分和添加物 .或是聚合物基質產生交互作用的問題，因而引發藥用產品毒理上 和藥理活性上的問題。此外，添加劑在製造過程中會保留活性成 分於微粒中，同時也可能在投與微粒後防止活性成分連續釋放而 影響活性物質的後續釋放情況。 其他用於微膠囊包覆技術的方法也已在使用混合有機溶劑的 基礎上陸續研發，試圖提高將活性分子以微膠囊技術包封在微粒 裡的效率，但這種方法卻會造成活性成分在微粒製作過程中的穩 定性問題。 2-丙基戊酸（2-Propylpentan〇ic acid)，俗稱丙戊酸 (Valproic acid，VPA )，其隨胺基化合物(vaipr〇mide，vp〇)和 某些鹽類和醋酸可有效治療癲癎（epi iepSy)或可作為抗精神病 樂。美國專利第4,988,731號(11.8.?&七此.4,988,731)揭露了 丙戊酸與二丙戊酸納之寡聚合物（〇Hg ome r)以1:1之分子比例形 ® 成4個單位結構，而美國專利第5,212,326號（U.S· Pat. No. 5, 212, 326)揭示一穩定且非吸濕性固體形式之丙戊酸，其中包含 以1:1分子比例結合的丙戍酸鈉與丙戊酸之募聚合物（oligomer) 並將此結構擴張至四〜六個單位。戴弗普斯納(J)ivalpr〇eX S〇(^iUm) 8 200815052 疋目刚世界上最廣泛接受的抗癲癇藥物之一。 錢’ Μ丙舰财治_財縣效，但钱期卻短於 /、匕令用之抗癎劑。依據報導，丙戊酸在成人體内之半衰期為6至 • 17小時之間，在兒童為細個小時之間，這將造成血聚中藥物濃 度的大幅波動，特別是對長期投藥而言。 . 為了克服此缺點，研發人員們專心致力於開發可在服藥後維 持丙戊自欠在血水中此更恒定的新型製劑。最終的研究目標是希望 可以藉由-天__服藥次數提供血漿中穩定的藥物濃度。基於 上述朋概使活性成分紐慢職於人體進行新陳代謝的 _ 製劑是必須的。 戴弗普斯納(Divalproex sodium)雖然已有各種形式的藥品製 劑發表，但配方改進仍是需要研究和必要的。 美國專利第5,⑽9, 897號(U.S· Pat. No· 5, 009, 897)揭示一 適合擠壓成藥錠之顆粒，此顆粒包含具戴弗普斯納之核心與一由 ’ 聚合物和微晶纖維素(microcrystalline cellulose)組合之塗層。 美國專利第 5, 019, 398號（U.S· Pat· Να 5, 019, 398)揭示以 一丙稀酸與丙戊酸納1 :1比例混合之緩釋片（sustaine(j_reiease 鲁 tablet) ’添加水合氧化石夕(hydrated silica，Levilite⑧)賦型劑 與經丙基曱基纖維素(hydroxypropyl methycellulose)為基質， 並以丙烯酸甲酯衍生物（Eudragit E 100，Eudragit NE 30)與瘦 丙基曱基纖維素(HPMC)作為膜衣材料。 200815052 美國專利第5, 055, 306號(U.S. Pat. No. 5, 055, 306)揭示可 供多種治療製劑所使用之發泡劑（effervescent)，或者屬於水崩 散性顆粒（water-d i spers i b 1 e granu 1 ar)之緩釋劑（susta i ned release formulation)。該顆粒包括活性成份和至少一種賦形劑 (excipient)的核心，以及由丙烯酸乙酯（ethyl acrylate)及曱基 丙稀酸甲酯和水溶性經基纖維素(hydroxylated cellulose)衍生 物組成之共聚合物（copolymer)形成一與水不溶，水膨脹之塗層。 美國專利第5,169, 642號(U.S· Pat. No. 5,169, 642)揭示一 種包括戴弗普斯納、丙戊醯胺或丙戊酸酯的顆粒，且覆蓋著由乙 • 烧基纖維素（ethyl cellulose)或丙稀酸甲酯、塑化劑 (plasticizer)、防沾黏劑（detackifying)、缓釋聚合之黏稠劑 (如羥丙基甲基纖維素和曱烷基纖維素）所組成之緩釋組合物。 美國專利第5, 589,191 號(U.S· Pat. No· 5, 589,191)揭示一 緩慢釋放之丙戊酸鈉之配方，其中藥錠是由乙烷基纖維素（ethyl cellulose)和石夕酸針（siHcic acid anhydride)所包覆。 美國專利第6, 610, 326號揭示一戴弗普斯鈉緩釋片。其製造藥 鍵的過程包含利用結合戴弗普斯鈉在水溶液和鹼作用以中和戴弗 鲁晋斯納，其中驗是用來中和戴弗普斯納的丙戊酸基。被中和後的 戴弗普斯鈉可噴灑於藥學上可接受之載體(carrier)，然後進一步 得到戴弗普斯鈉緩釋藥錠。 美國專利第6,419,953號(U.S· Pat· Να 6,419,953)揭示一 200815052 親水性之基質錠片可適用於戴弗普斯鈉一天一錠之配方，其中這 親水性基質疋經丙基甲基纖維素（hydroxypropyl methylcellulose) 〇 • 不過’吸潮干擾(hygroscopicity interferes)和戴弗普斯納 之黏性仍然是主要問題。這些特性導致需要在製造戴弗普斯鈉藥 錠過程中限制相對濕度(relatively humidity)。在某些情況下， 相對濕度須維持在55〜60 %，甚至少於3〇 % (美國專利第 4, 913, 906號，美國專利第5, 017, 613號，與美國專利第 5,185, 159號），這種情形不利於戴弗普斯鈉商品化。為了克服戴 _ 弗普斯鈉黏㈣題，錢案件也揭示加人抗鋪或防沾黏劑。 美國專利第 5,185,159號(U.S· Pat· No. 5,185,159)揭示 一種無黏合劑（binder)或造粒溶劑（granuiating solvent)的丙戊 酸和丙戊酸鈉製劑。該製劑視情況選擇沉澱矽石（precipitated slllca)作為抗黏劑或防沾黏劑，並以聚維酮（polyvidone)或丙 ' 稀酸甲酯（methacrylate)作為塗層。 【發明内容】 本發明提供一控制釋放之組合物，包含具均勻狀態之疏水性 纖維素、甲基丙騎共聚物和活性成份。用於本發明疏水性纖維 素疋種具疏水能力的纖維素。在一個較佳的實施例，疏水性纖 維素是乙烷基纖維素，其中乙烷基纖維素的黏度由3至120黏度m Pa s (cp)。在一個較佳的實施例，乙烷基纖維素的黏度是從2〇 200815052 至110黏度m Pa s (cP)。在一個更佳的實施例，乙烧基纖維素 的黏度是由90至110黏度m pa s (cp)。 用於本發明組合物之甲基丙烯酸共聚物是甲基丙烯酸 • (methacryHc acid)與甲基丙烯酸甲酯（肥仕^1 methacjfyiayte) 之共I物。在-個較佳的實施例，甲基丙烯酸與甲基丙烯酸甲酯 •的比例為3:1至1:3。在一個更佳的實施例，這個比例是1:2至 2.1。商業上甲基丙燦酸共聚物可以為尤特奇⑽ragitS1〇〇)。 本發明之活性成分可以為化學化合物、醫藥組合物、或生物 衣藥組合物。在-個較麵實施例，活性成分是齡普斯納。在 ® 個更佳的貫施例，戴弗普斯鈉含量佔組合物重量25%至55%。 就本發明之組合物而言，财性纖維素和甲基丙稀酸共聚物 的比例為10·1至1.10。在一個較佳的實施例，兩者的比例是ϋ 到1:3。在一個更佳的實施例，比例為12:1。按上述比例的本發 •明組合物可賴令人驚_絲。詳言之，是在接觸水或人造模 •擬腸溶㈣，本組合物會軸—可贿微雌成分之多孔半渗 透基質。 由於混合物中的活性成分(如戴弗普斯納)和甲基丙缚酸共聚 鲁物容易引發吸潮Owoscopicito，在製鍵的過程時，它會將活 性成分黏著翁_沖模上。為了解決麟問題，本發赚用乙 烧基纖維素包_造粒之微麵包賊術。因此，本發明組合物 更進-步包含乙院基纖維素作為膠囊包覆的外膜。乙烧基纖維素 200815052 是-種疏水性纖維素，可用於形成薄膜覆蓋組成份。在一個較佳 :實施例’乙燒基纖維素包覆在組合物外膜含量範_組合物重 里0. 5%至1G%。在-個更佳的實關’乙錄纖維素包覆組合物外 膜含置範圍佔組合物重量1%至观。 . 身又來况’壓織劑需要低於3〇 %的相對濕度。當處於40—60 %的相對濕度時，报難將壓錠製劑的製程規模化。^了克服在相同 條件下吸潮和黏著_題，本發明之組合物進—步包含二氧化石夕 (silicon dioxide)、硬脂酸鎂（magnesium stearate)、鎂鋁矽酸 鹽（magnesium aluminum silicate)。在一個較佳的實施例，二氧 ♦化碎的含量佔組合物重〇.1%細，其中硬脂酸鎮含量佔組合物重 〇· 1%至4%，而鋁鎂矽酸鹽含量幅度佔組合物重〇· 1%至4%。 本組合物可在液體狀態下控制釋放，並可用於作藥劑上治療 病患。 本發明亦提供一種用於生產控釋錠型方法，包括(8)混合疏水 • 性纖維素、甲基丙烯酸共聚物和活性成分成均勻混合物；（b)噴塗 疏水性纖維素至混合物，以形成微膠囊顆粒；（c)喷塗黏合劑溶液 至微膠囊顆粒形成粒狀·’（d)加入二氧化矽、硬脂酸鎂、鋁鎂矽酸 ® 鹽至微膠囊顆粒混勻成錠。本方法更進一步包括利用膜衣噴液 (Opadry Π white)之色料塗層技術。在一個較佳的實施例，疏水 性纖維素是乙烷基纖維素。 在一個實施例中，甲基丙烯酸共聚物是是甲基丙烯酸與甲基 200815052 是i疏水性纖維素’刊於形賴顧蓋喊份。在—個較佳 =實施例，乙《纖維素包覆在組合物外膜含量細佔組合物重 量〇· 5%至應。在-個更佳的實施例，乙烧基纖維素包覆組合物外 ^ 膜含量範圍佔組合物重量1%至3%。 • —般來說，壓錠製劑需要低於30 %的相對濕度。當處於4〇一6〇 %的相對謎時，很難將壓錠製劑的縣規模化。丨了克服在相同 條件下吸潮和黏著的問題，本發明之組合物進一步包含二氧化石夕 (silicon dioxide)、硬脂酸鎂（magnesium stearate)、鎂鋁矽酸 鹽（magnesium aluminum silicate)。在一個較佳的實施例，二氧 *化石夕的含量佔組合物重0.1%至⑽，其中硬脂酸鎮含量佔組合物重 0· 至’而|呂鎮石夕酸鹽含量幅度佔組合物重q. 1%至4%。 本組合物可在液體狀態下控制釋放，並可用於作藥劑上治療 病患。 本發明亦提供一種用於生產控釋錠型方法，包括化)混合疏水 ^ 性纖維素、甲基丙烯酸共聚物和活性成分成均勻混合物；（b)噴塗 疏水性纖維素至混合物，以形成微膠囊顆粒；（c)噴塗黏合劑溶液 至微膠囊顆粒形成粒狀；（d)加入二氧化矽、硬脂酸鎂、鋁鎂矽酸 穩|鹽至破膠囊顆粒混勻成疑。本方法更進一步包括利用膜衣喷液 (Opadry II White)之色料塗層技術。在一個較佳的實施例，疏水 性纖維素是乙烷基纖維素。 在一個實施例中，甲基丙烯酸共聚物是是甲基丙烯酸與甲基 200815052 丙稀1甲1之共*物。在_個較佳的實施例，曱基丙稀酸與甲基 丙烯酸甲酷的比例為3:1至1:3。在-個更佳的實施例，這個比 例是1:2至2:1。在-個最佳的實施例，這個比例是^。 • 本發明之活性成分可簡化學化合物、醫藥組合物 、或生物 製藥組合物。在-個較佳的實施例，活性成分是戴弗普斯納。 在-個貫施例中，疏水性纖維素和曱基丙稀酸共聚物的比例 為10 · 1至1 · 10。在一個較佳的實施例，兩者的比例是3 : : 3。在一個更佳的實施例，比例為n】。 在-個更佳的實施例中，按本發明方法所製備控釋藥錠包含約 _ 53· 8重量百分比戴弗普斯鈉；、約17•了重量百分比乙絲纖維素； 約14.1重量百分比甲基丙烯酸共聚物；約5 6重量百分比微晶纖 維素；約0.8重量百分比聚乙烯；4重量百分比二氧化矽；約2 重里百分比硬脂酸鎭，約2重量百分比銘鎮石夕酸鹽；以及約有3 重量百分比含膜衣噴液(Opadry II white)。 - 本發明之方法可更有效生產控釋錠劑。 本發明的特點和優點對於閱讀以下詳細說明之本領域習之技 藝之人可以更容易了解。本發明值得讚賞的某些特徵，具有明確 # 的原因，上下文所述及分列的實施例，亦可合併為一個單一的實 施例。相反的，本發明的各種特色，為了簡潔的理由，在本文中 敘述為一個單一的實施例，也可從原本結合的形式視為分開的組 合。 200815052 除非特別說明，否則本文中提到的奇數也可能包括複數。例 如’"一"，可能是指任一個或多個。 本文所列定義於此凌駕於任何專利，專利申請和/或專利申往 公開書所引據參考文獻所列之定義。 【實施方式】 下面的例子非限制性，只是代表本發明對各方面不同的觀 點與特性。 材料 樂鍵核心（小計1000毫克） 毫克 % 戴弗普斯納 538. 0 53.8 乙烷基纖維素 lOOcps FP 176.5 17.7 微晶纖維素 56.3 5.6 —---- 硬脂酸鎂 20.0 2.0 ~__ 乙醇 溶劑 尤特奇 S -100 —·. 聚維_ j3〇 亳克 141.2 14· 1 8.0A particle core comprising a pharmaceutically active ingredient and a coating that substantially covers the entire core surface, wherein the coating comprises ethyl acrylate and methyl methacrylate, and a water-soluble hydroxycellulose derivative A natural copolymer composed of a hydroxylated cellulose derivative, etc., which is a thin layer that is insoluble in water but expands when exposed to water. U.S. Patent No. 4,952,402 (U.S. Pat. Water-soluble, permeable, impermeable, biodegradable control, or a mixture of these. Most controlled release ingredients or dosage forms consist of two parts, the core and the coating. The core contains active ingredients and excipients. There are many variations in the coating material in terms of its knives, composition ratio, solubility, hydrophobicity or hydrophilicity. Different formulations and process parameters can be combined in a variety of ways to optimize the release of the release (eg number of layers of coating, type and amount of plasticizer added). The form in which the active ingredient is released from the core is gradually being explored, and a liquid-insoluble liquid suspension, 6 200815052 mixed with an enteric polymer for use in the coating of tablets is also under investigation, such as B. Ethyl cellulose: hydroxypropyl methycellulose acetate succinate (EC ··HPMCAS) and ethyl cellulose: ethyl acrylate copolymer) (EC: Eudragit L) (F. Siepmann et 5/, 2005, /· You/I see 1〇5: 226-239). One of the main problems with controlled release preparations is that they release a large amount of active ingredient within the first hour after administration. Usually, such a release result will cause a sudden increase in the concentration of the drug in the blood. Such a situation can, in many cases, cause the body to be unacceptable and cause toxicity problems. On the other hand, since a large amount of active substance is suddenly and rapidly released after administration, the residence time of the active pharmaceutical ingredient is also lowered. The first question is that when using the conventional coating technique of microcapsules (micr〇encapsUiati〇n), a relatively inefficient encapsulation rate is often obtained, especially when the active ingredient is a water-soluble pharmaceutical product. - The third side problem must be solved in the development of these distributions, which will cause instability of the active ingredients, because the active ingredients need to face harsh conditions in the production of microparticles (such as high temperature or in the dissolution of the cracks) The step will be in contact with the organic solvent for a long time. In order to solve the above problems, many experiments have been conducted. Therefore, some of the added ft like sugar, oil wax, soil, protein, polymer, salt or acid have been used in her agent shouting __ml_phere) towel, material _ 丨, is to keep the 200815052 medicinal product in the particles Substance can increase the efficiency of microencapsulation technology and, if possible, protect the active ingredient and act as a stabilizer during encapsulation. • However, the addition of these additives to the microparticles can cause problems with the interaction of the active ingredient and the additive or the polymer matrix, thus causing problems in the toxicological and pharmacological activities of the medicinal product. In addition, the additive retains the active ingredient in the microparticles during the manufacturing process, and may also prevent continuous release of the active ingredient after administration of the microparticles, thereby affecting subsequent release of the active material. Other methods for microcapsule coating technology have been developed on the basis of using mixed organic solvents, in an attempt to improve the efficiency of encapsulating active molecules in microparticles in microparticles, but this method results in active ingredients. Stability issues during particle making. 2-Propylpentan〇ic acid, commonly known as Valproic acid (VPA), is effective in treating epilepsy with amino compounds (vaipr〇mide, vp〇) and certain salts and acetic acid.癎 (epi iepSy) may be used as an antipsychotic. U.S. Patent No. 4,988,731 (11.8.?), pp. 4,988,731, discloses valeric acid and bismuth valerate oligopolymer (〇Hg ome r) in a molecular ratio of 1:1 to 4 units. U.S. Patent No. 5,212,326 (U.S. Pat. No. 5,212,326), the disclosure of which is incorporated herein by reference to the entire entire entire entire entire entire entire entire entire entire entire entire content Polymer with valproic acid (oligomer) and expand this structure to four to six units. Dave Pusner (J) ivalpr〇eX S〇 (^iUm) 8 200815052 One of the world's most widely accepted anti-epileptic drugs. Money Μ Μ 舰 舰 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ According to reports, the half-life of valproic acid in adults is between 6 and 17 hours, which is a small hour between children, which will cause large fluctuations in the concentration of blood in the drug, especially for long-term administration. In order to overcome this shortcoming, researchers have devoted themselves to the development of new formulations that maintain a more constant rate of acetophenone in blood after administration. The ultimate goal of the study was to provide a stable concentration of plasma in the plasma by the number of doses administered. Based on the above-mentioned factors, it is necessary to make the active ingredient to be used in the human body for metabolism. Although Divalproex sodium has been published in various forms of pharmaceutical preparations, formulation improvements are still necessary and necessary. US Patent No. 5, (10) 9,897 (US Pat. No. 5, 009, 897) discloses a granule suitable for extrusion into a tablet comprising a core of Duffus and a polymer and A coating of a combination of microcrystalline cellulose. US Patent No. 5, 019, 398 (US Pat. No. 5, 019, 398) discloses a sustained release tablet (sustaine (j_reiease ru tablet) added with a ratio of acrylic acid to sodium valproate in a ratio of 1:1. Hydrated silica (Levilite 8) excipient and hydroxypropyl methy cellulose as matrix, and methyl acrylate derivative (Eudragit E 100, Eudragit NE 30) and lean propyl sulfhydryl Cellulose (HPMC) is used as a film coating material. US Patent No. 5, 055, 306 (US Pat. No. 5, 055, 306) discloses an effervescent that can be used in various therapeutic preparations, or belongs to a water-d i spers ib 1 e granu 1 ar release release formulation comprising a core of an active ingredient and at least one excipient, and an acrylic acid A copolymer composed of ethyl acrylate and methyl mercaptomethyl acrylate and a water-soluble hydroxylated cellulose derivative forms a water-insoluble, water-swellable coating. 5,169,642 (US· Pat. N o. 5,169,642) discloses a granule comprising Duffusner, valproate or valproate, covered with ethyl cellulose or methyl acrylate, plasticized A sustained release composition consisting of a plasticizer, a detackifying, a slow release polymeric binder such as hydroxypropylmethylcellulose and a decylcellulose. U.S. Patent No. 5,589,191 (US Pat. No. 5, 589, 191) discloses a slow release sodium valproate formulation in which the tablet is coated with ethyl cellulose and siHcic acid anhydride. U.S. Patent No. 6,610,326 discloses a Defoggs sodium sustained release tablet. The process of making a drug bond involves neutralizing Defoe Jinsner in combination with Defom Sodium in aqueous solution and alkali. The test is used to neutralize the valproic acid group of Defopsner. The neutralized Duffus sodium can be sprayed onto a pharmaceutically acceptable carrier, and then further defogged sodium is obtained. Released ingots. U.S. Patent No. 6,419,953 (US Pat. No. 6,419,953) discloses a 200815052 hydrophilic The base tablet can be applied to the formulation of Daphus sodium one day, wherein the hydrophilic matrix is hydroxypropyl methylcellulose 〇 • However, hygroscopicity interferes and Defopp Sna's stickiness is still the main problem. These characteristics have led to the need to limit the relative humidity during the manufacture of the Daphups sodium tablet. In some cases, the relative humidity must be maintained at 55 to 60%, or even less than 3% (U.S. Patent No. 4,913,906, U.S. Patent No. 5,017,613, and U.S. Patent No. 5,185,159 No.) This situation is not conducive to the commercialization of Duffus sodium. In order to overcome the problem of wearing _ 弗普斯 sodium sticky (four), the money case also reveals the addition of anti-paste or anti-adhesion agent. U.S. Pat. No. 5,185,159 discloses a valproic acid and sodium valproate formulation without a binder or granuiating solvent. The formulation optionally employs precipitated stellite as an anti-adhesive or anti-adherent agent and is coated with polyvidone or methacrylate. SUMMARY OF THE INVENTION The present invention provides a controlled release composition comprising a hydrophobic cellulose, a methyl methacrylate copolymer and an active ingredient in a uniform state. It is used in the hydrophobic cellulose of the present invention to have a hydrophobic ability of cellulose. In a preferred embodiment, the hydrophobic cellulose is ethane-based cellulose wherein the ethane-based cellulose has a viscosity of from 3 to 120 vis m Pa s (cp). In a preferred embodiment, the viscosity of the ethane-based cellulose is from 2 〇 200815052 to 110 viscosities m Pa s (cP). In a more preferred embodiment, the viscosity of the ethyl ketone cellulose is from 90 to 110 viscosities m pa s (cp). The methacrylic acid copolymer used in the composition of the present invention is a combination of methacrylic acid (methacry Hc acid) and methyl methacrylate (fabric ^1 methacjfyiayte). In a preferred embodiment, the ratio of methacrylic acid to methyl methacrylate is from 3:1 to 1:3. In a preferred embodiment, the ratio is 1:2 to 2.1. Commercially available methacrylic acid copolymers can be Eudragit (10) ragitS1(R). The active ingredient of the present invention may be a chemical compound, a pharmaceutical composition, or a biopharmaceutical composition. In a comparative example, the active ingredient is aged Psna. In a better example, the Daphus sodium content is 25% to 55% by weight of the composition. For the composition of the present invention, the ratio of the financial cellulose to the methyl methacrylate copolymer is from 10.1 to 1.10. In a preferred embodiment, the ratio of the two is 1 to 1:3. In a preferred embodiment, the ratio is 12:1. According to the above ratio, the composition of the present invention can be astonishing. In particular, it is in contact with water or artificial molds • It is intended to be enteric (4), and the composition will be a porous semi-permeable matrix of brittle micro-ingredients. Since the active ingredients in the mixture (such as Defopsner) and the methyl acrylate acid copolymer are prone to cause moisture absorption Owoscopicito, it will adhere the active ingredient to the die during the bonding process. In order to solve the problem of Lin, the company earned the use of B-based cellulose pack _ granulation micro-bread thief. Accordingly, the composition of the present invention further comprises a hospital-based cellulose as a capsule-coated outer film. Ethylene-based cellulose 200815052 is a kind of hydrophobic cellulose that can be used to form a film covering component. 5%至1格百分比。 In a preferred embodiment of the composition of the outer film of the composition of the composition of the composition of the composition of the composition of In a better practice, the film coverage of the B-coated cellulose coating composition ranges from 1% by weight of the composition. The body pressure condition requires a relative humidity of less than 3%. When it is at a relative humidity of 40-60%, it is difficult to report the scale of the tablet preparation process. Overcoming the moisture absorption and adhesion under the same conditions, the composition of the present invention further comprises silicon dioxide, magnesium stearate, magnesium aluminum silicate (magnesium aluminum silicate). ). In a preferred embodiment, the amount of dioxin is about 1% fine, wherein the stearic acid content is from 1% to 4% by weight of the composition, and the aluminum magnesium citrate content The range is from 1% to 4% of the composition. The composition can be controlled to release in a liquid state and can be used as a medicament for treating a patient. The present invention also provides a method for producing a controlled release ingot comprising (8) mixing a hydrophobic cellulose, a methacrylic acid copolymer and an active ingredient into a homogeneous mixture; and (b) spraying a hydrophobic cellulose to the mixture to form Microcapsule particles; (c) spraying the binder solution to the microcapsule particles to form a granule. '(d) adding cerium oxide, magnesium stearate, aluminum magnesium citrate® salt to the microcapsule particles and mixing into an ingot. The method further includes the use of a pigment coating technique of Opadry® white. In a preferred embodiment, the hydrophobic cellulose is ethane-based cellulose. In one embodiment, the methacrylic acid copolymer is methacrylic acid and methyl 200815052 is i hydrophobic cellulose. In a preferred embodiment, B. The cellulose coating on the outer film of the composition accounts for a fine amount of 5% of the composition. In a more preferred embodiment, the ethyl ketone cellulose coating composition has a film content ranging from 1% to 3% by weight of the composition. • In general, tablet formulations require less than 30% relative humidity. When it is in the relative mystery of 4〇6〇%, it is difficult to scale the county of the tableting preparation. In order to overcome the problem of moisture absorption and adhesion under the same conditions, the composition of the present invention further comprises silicon dioxide, magnesium stearate, magnesium aluminum silicate. In a preferred embodiment, the content of dioxin* fossils is 0.1% to (10) by weight of the composition, wherein the stearic acid content is 0 to ～ of the composition and the content of the Lvcheng sulphate is as large as the composition. q. 1% to 4%. The composition can be controlled to release in a liquid state and can be used as a medicament for treating a patient. The invention also provides a method for producing a controlled release ingot comprising: mixing a hydrophobic cellulose, a methacrylic acid copolymer and an active ingredient into a homogeneous mixture; (b) spraying the hydrophobic cellulose to the mixture to form a micro Capsule granules; (c) spraying the binder solution until the microcapsule particles form granules; (d) adding cerium oxide, magnesium stearate, aluminum magnesium citrate stabilized salt to the broken capsule particles and mixing them into doubt. The method further includes the use of a pigment coating technique of Opadry II White. In a preferred embodiment, the hydrophobic cellulose is ethane-based cellulose. In one embodiment, the methacrylic acid copolymer is a combination of methacrylic acid and methyl 200815052 propylene 1 . In a preferred embodiment, the ratio of mercaptoacrylic acid to methyl methacrylate is from 3:1 to 1:3. In a preferred embodiment, this ratio is 1:2 to 2:1. In the preferred embodiment, this ratio is ^. • The active ingredient of the present invention may be a simplified compound, a pharmaceutical composition, or a biopharmaceutical composition. In a preferred embodiment, the active ingredient is Defopsner. In one embodiment, the ratio of the hydrophobic cellulose to the mercaptoacrylic acid copolymer is from 10 · 1 to 1 · 10. In a preferred embodiment, the ratio of the two is 3::3. In a more preferred embodiment, the ratio is n]. In a more preferred embodiment, the controlled release tablet prepared according to the method of the present invention comprises about _5.38% by weight of Defompress sodium; about 17% by weight of Ethylcellulose; about 14.1% by weight a methacrylic acid copolymer; about 56 weight percent microcrystalline cellulose; about 0.8 weight percent polyethylene; 4 weight percent cerium oxide; about 2 weight percent strontium stearate, about 2 weight percent of ingzhen And about 3 weight percent of the film spray (Opadry II white). - The method of the invention makes it possible to produce controlled release tablets more efficiently. The features and advantages of the present invention will become more apparent to those skilled in the art in the <RTIgt; Some of the features that are appreciated by the present invention, with the explicit #, the context and the listed embodiments, may also be combined into a single embodiment. On the contrary, the various features of the invention are described herein as a single embodiment for the sake of brevity, and may be considered as a separate combination from the original combination. 200815052 Unless otherwise stated, the odd numbers mentioned in this article may also include plurals. For example, '"一" may refer to any one or more. The definitions set forth herein are defined above in the references cited in any patent, patent application and/or patent application. [Embodiment] The following examples are not limiting, but represent different viewpoints and characteristics of the present invention in various aspects. Material key core (subtotal 1000 mg) mg% Defopsner 538. 0 53.8 Ethyl cellulose lOOcps FP 176.5 17.7 Microcrystalline cellulose 56.3 5.6 —---- Magnesium stearate 20.0 2.0 ~__ Ethanol solvent Utech S-100 —·. 聚维_ j3 〇亳克 141.2 14· 1 8.0
0.B 20.0 40.0 溶劑 200815052 彩色膜衣（小計30毫克) 膜衣噴液 Opradry II white (85G28725) 30.0毫克 3% 乙醇 溶劑 純水 溶劑 實施例一製備核心錠劑（10, 000錠) 混合的成分如下列所示： 戴弗普斯鈉 5380 克 乙烷基纖維素lOOcps FP 1665 克 尤特奇⑧S-100 1412 克 微晶纖維素 563 克 將其用孔徑30的篩網過濾，並在強攪拌器（supermixer)下以 120轉速(rpm)攪拌10分鐘然後得到均質的粉末。 實施例二微膠囊包覆製程 (a) 微膠囊包覆溶液之製備0.B 20.0 40.0 Solvent 200815052 Color film coat (subtotal 30 mg) Film spray Opradry II white (85G28725) 30.0 mg 3% Ethanol solvent Pure water solvent Example 1 Preparation of core lozenge (10, 000 ingots) Mixed ingredients As shown below: Duffus Sodium 5380 g Ethyl cellulose lOOcps FP 1665 Kyutech 8S-100 1412 g Microcrystalline cellulose 563 g Filtered with a sieve of pore size 30, and in a strong agitator (supermixer) was stirred at 120 rpm for 10 minutes and then a homogeneous powder was obtained. Example 2 Microcapsule coating process (a) Preparation of microcapsule coating solution
Rx: 益多秀膠體(Ethocel® 100 cps FP) 100 克 乙醇 1.6公升 純水 200毫升 將乙烷基纖維素置於含有乙醇和純水的溶液中。該溶液利用 200815052 攪:摔子(stirrer)混合均勻直到乙说基纖維素完全溶解。 (b)微膠囊包覆 將均貝粉末（貫施例一）放進流動床(Wurster f bed)。操 - 作條件設立為：入口溫度70°C，出口溫度35°C，喷霧速率：40〜80 ★ 耄升/每分鐘，預熱時間：5分鐘。喷灑微膠囊包覆溶液至均質粉 末’然後得到微膠囊化顆粒(micr〇encapulati〇n gramiles)。 實施例二造粒（Granu 1的丨〇n) (a)黏合劑溶液(]3iri(jer> s〇iuti〇n)之製備: • Rx: 80 克 320毫升 600毫升 聚維酮(Povidone K-30) 乙醇 純水 將聚維酮(Povidone K-30)置於含有乙醇和純水的溶液中。該 '溶液利用搜拌子⑽贿)混合均勻直到聚維嗣⑽他此κ_3〇) 完全溶解。 ^ (b)造粒方法 將微膠囊化顆粒（實例二）放進流動床（Wurster fluid bed)。操作條件設立為：人口溫度肌出口溫度35χ：，喷霧速率： 40〜80亳升/每分鐘，乾燥時間：5分鐘，最低檢測濃度（L 〇· d·) -< 3/°。贺赫合劑/〜肢轉囊化雛，織將其用孔徑20的篩 200815052 網過濾’即可取得戴弗普斯鈉顆粒。 實施例四混合完成與打鍵 (a )混合 混合的成分如下列所示： 戴弗普斯鈉顆粒 9200 克 二氧化矽 400克 鎂鋁合金矽酸鹽 200克 硬脂酸鎂 200克 總計： 10, 000 克Rx: Ethocel® 100 cps FP 100 g Ethanol 1.6 liters Pure water 200 ml Ethyl cellulose is placed in a solution containing ethanol and pure water. The solution was homogenized using 200815052: Stirrer until the base cellulose was completely dissolved. (b) Microcapsule coating A uniform shell powder (Example 1) was placed in a fluid bed (Wurster f bed). Operation - The conditions are set as follows: inlet temperature 70 ° C, outlet temperature 35 ° C, spray rate: 40 to 80 ★ soar / per minute, preheating time: 5 minutes. The microcapsule coating solution is sprayed to a homogeneous powder and then microencapsulated particles (micr〇encapulati〇n gramiles) are obtained. Example 2 Granulation (Granu 1 丨〇n) (a) Preparation of binder solution (3iri(jer> s〇iuti〇n): • Rx: 80 g 320 ml 600 ml povidone (Povidone K- 30) Ethanol pure water Put Povidone K-30 in a solution containing ethanol and pure water. The 'solution is mixed with the spar (10) and mix until the granules (10) κ_3〇) completely dissolved. . ^ (b) Granulation method The microencapsulated particles (Example 2) were placed in a fluid bed (Wurster fluid bed). The operating conditions were set as follows: population temperature muscle outlet temperature 35 χ:, spray rate: 40 to 80 liters per minute, drying time: 5 minutes, minimum detection concentration (L 〇 · d·) - < 3 / °. Hehe mixture / ~ limb transfer capsule, weaving it with a pore size of 20 sieve 200815052 net filtration ' can get Dafopuls sodium particles. The composition of the fourth embodiment mixed and mixed with the key (a) is as follows: Daphus sodium particles 9200 g of cerium oxide 400 g of magnesium aluminum citrate 200 g of magnesium stearate 200 g Total: 10, 000 grams
(538毫克戴弗普斯納/1咖毫克顆粒） 將以上的域成分放人雙錐觀合機(tobie _)以_ 速(聊)麟7分鐘。將在實施例三所得喊弗普斯_粒加入二 氧化石夕、纖魏鹽及硬麟鎂聰止在欣過程巾出現戴弗普 斯鈉之黏著問題。 (b)製錠 上述已完成混合之顆粒放進2〇轉之旋轉壓片機（rotat ing tabletting machine)。操作條件設立為··預壓qqq镑，主要壓 力 12, 000，轉速2〇rpm。 裸鍵規格如下： 重量：970亳克〜1030亳克(相當於具500毫克之丙戊酸鈉活性) 200815052 橢圓形藥錠形狀：18.9毫米χ 10毫米 厚度：8. 3毫米〜8.8毫米 硬度：13到25公斤。 實施例五彩色膜衣包覆 Rx: 樂錠核心 10, 000 克 Opradry II White (85G28725) 300 克 乙醇（溶劑） 970 毫升 純水（溶 2, 265 亳升 總計： 10, 300 克 (a) 彩色膜衣包覆溶劑之製備 將膜衣噴液(Opradry II white)置於含有乙醇和純水的溶液 中。該溶液利用攪拌子（stirrer)混合均勻直到膜衣噴液①pradry II white)形成均勻的狀態。 (b) 彩色膜衣塗層 將貫施例四所提之裸錠置入膜衣包覆盤 Coatlng pan)。操作條件設立為··人口溫度：75〜85°C，出口溫 度45 50 C，盤旋轉速度：2〜15轉速(rpin)，預熱時間：1〇分 鐘’噴射速率：100克/每分鐘，乾燥時間：5分鐘。喷塗彩色膜衣 200815052 育液至裸I定上形成膜衣。 所製錠劑每錠具重量1030毫克(相當於具有5〇〇毫克之丙戊酸 鈉活性）。 - 實施例六溶離測試 為了決定控釋敎的效果，進行溶離度的試驗。 戴弗普斯鈉緩釋片250毫克與5〇〇毫克進行試驗。溶離的情 況為在pH 6. 8磷酸鹽緩衝液中，在適當的授拌器中以ι〇〇轉速 (_的麟速度猶18個小時。藥錠的圖片如圖—和圖二所示， #包含藥縣測試前(見圖一⑷和圖二⑷）以及測試後（見圖- ⑹和圖二⑹）。藥錠橫斷面的圖片也可見於圖一⑹和圖二 ⑹。圖3顯示戴弗普斯鈉緩釋藥鍵测毫克在溶離試驗下的釋放 圖表。根據溶離度試驗的結果，可以报清楚顯示本藥旋具有良好 的緩釋效果。 雖然本發明之製造與制，為熟悉本躺之技藝人士做充分 詳細的描述和舉例佐證，但各種替代、修改與改進均不應該明顯 背離的本發明之精神和範圍。 —熟悉本技藝之人士很容易可以#識到，本發明不僅完全符合 貫現本發明計晝與制所提的目標射獅件，同時也保有原本 應存在之原S ^王與方法為生產本發明較佳實施例的代表，堪 稱舉例，並非為意_為本發社關。本領域習之技藝之 人可就此進鄕改與任何_。但·修_包含在本發明的精 20 200815052 神與本發明所界定的權利範圍中。 就本領域習之技#之人㈣，對於在此的本發明有任何 的心改婦代’難地都不會偏離本發明之精神和範圍。 . 在本制書所提及的任何專顺出版儀_示了本發明所 •屬倾㈣之技藝程度。所有糊與出版所提及的參考索引 如同個別單-指出的公開刊物或個人創作作為本發明之參酌。 本發明在此的敘述朗可翻於實施上缺少任何在此未特別 揭露之單-元素或域，以及單—限制柄限。在此所使用的任 何用顯錢是作林域述的辭句，轉關，因此於此所使 用的用詞與表達並無意圖排除任何鱗於本文所提之特點、敛述 與部份内容，但是也應該承認不同輸铸是本個可能的權利 關。因此，應該認識到賴目前的發明已明·露較佳的實施 ρ射聊㈣點，但是纽透露姐造和變倾概念可能會為 ’、〜本技#之人士所抓用’所以這些修改與變動都被視為本發明 的範圍，亦界定於本發明之權力範圍。 其他的具體實施例載於下列切專利範圍。 200815052 【圖式簡單說明】 顯示控釋測試結果，250毫克戴弗普斯鈉缓釋片（a )指所 製備錠劑之外觀；（b)指在溶離測試18小時下鍵劑之外 觀；（c)係溶離試驗18小時下該錠劑之橫斷面。(538 mg Defopsner / 1 gamma granules) Put the above ingredients into a double cone machine (tobie _) to _ speed (talk) Lin 7 minutes. In the third embodiment, the spurs of the spurs were added to the sulphur dioxide, the sulphur, and the hard sulphate. (b) Ingot The above-mentioned mixed granules were placed in a 2 rotating tableting machine. The operating conditions were set to pre-press qqq pounds with a main pressure of 12, 000 and a speed of 2 rpm. The bare key specifications are as follows: Weight: 970 gram ~ 1030 gram (equivalent to 500 mg of sodium valproate activity) 200815052 Oval shape: 18.9 mm χ 10 mm Thickness: 8. 3 mm ~ 8.8 mm Hardness: 13 to 25 kg. Example 5 Colored film coat coated Rx: Lozen core 10, 000 g Opradry II White (85G28725) 300 g ethanol (solvent) 970 ml pure water (dissolved 2, 265 liters total: 10, 300 g (a) color Preparation of film coating solvent A film spray (Opradry II white) is placed in a solution containing ethanol and pure water. The solution is uniformly mixed with a stirrer until the film spray 1pradry II white forms a uniform status. (b) Color film coating The bare ingots of Example 4 were placed in a film coating plate Coatlng pan). The operating conditions are set as ·· Population temperature: 75~85°C, outlet temperature 45 50 C, disk rotation speed: 2~15 rotation speed (rpin), preheating time: 1〇 minutes' injection rate: 100g/min, Drying time: 5 minutes. Spray color film coat 200815052 Develop a film coat from the culture solution to the bare I. The tableting agent has a weight of 1030 mg per tablet (equivalent to having 5 mg of sodium valproate activity). - Example 6 Dissolution Test In order to determine the effect of controlled release enthalpy, a test for the degree of dissolution was carried out. Daveps sodium sustained release tablets were tested at 250 mg and 5 mg. The dissolution is in the pH 6. 8 phosphate buffer, in the appropriate mixer, at the speed of 〇〇 (the speed of _ is 18 hours. The picture of the tablet is shown in Figure - and Figure 2, #Included before the drug county test (see Figure 1 (4) and Figure 2 (4)) and after the test (see Figure - (6) and Figure 2 (6)). The picture of the cross section of the tablet can also be seen in Figure 1 (6) and Figure 2 (6). Figure 3 The release profile of the Daverp sodium sustained release drug bond in the dissolution test is shown. According to the results of the solubility test, it can be clearly shown that the drug has a good sustained release effect. Although the manufacture and manufacture of the present invention, A person skilled in the art will be fully described and exemplified by the detailed description and examples, but the various alternatives, modifications, and improvements are not intended to be clearly departing from the spirit and scope of the present invention. - Those skilled in the art can readily recognize that the present invention Not only is it fully consistent with the target lion shooting parts of the present invention, but also the original S ^ king and method that should exist in order to produce the representative embodiment of the preferred embodiment of the present invention, which is an example, not intended _This is the social agency. The person may tamper with any _. However, it is included in the scope of the rights defined by God and the present invention. The person in the field (4), for the person here The invention has any mentality to change the woman's difficulty without departing from the spirit and scope of the invention. Any of the specialized publications mentioned in this booklet shows the degree of skill of the invention. All references and references cited in the publication are as individual lists - pointed out publications or individual creations as a discrepancy of the present invention. The description of the invention herein is in the absence of any single-element not specifically disclosed herein. Or domain, and single-restricted handle. Any use of the explicit money used here is a statement of the forest domain, and the words and expressions used herein are not intended to exclude any scales. The characteristics, arbitrage and part of the content, but it should also be acknowledged that different castings are the possible rights. Therefore, it should be recognized that the current invention has clearly demonstrated the implementation of ρ Talk (4), but New Zealand reveals that the concept of sister creation and change is possible It will be understood that the scope of the present invention is defined by the scope of the present invention and the scope of the present invention is defined by the following claims. [Simple description of the diagram] The controlled release test results are shown, 250 mg of Defoggs sodium sustained release tablets (a) refers to the appearance of the prepared tablet; (b) refers to the appearance of the key agent after 18 hours of the dissolution test; ) is a cross section of the tablet at 18 hours of the dissolution test.
顯示500毫克的戴弗普斯鈉接雜^ —也丨碰® / 圖 指該所製備錠劑之外觀； 之外觀；（c)係溶離試驗1〇个砰下該錠劑之橫斷面 顯不戴弗普斯鈉500毫克緩釋片在溶離試驗下之釋故图 22Shows 500 mg of Defom Sodium in combination ^ - also Bumper ® / Figure refers to the appearance of the prepared lozenge; appearance; (c) is the dissolution test of the lozenge of the lozenge Discharge of the Disuves sodium 500 mg sustained-release tablet under the dissolution test Figure 22